Dietary Fat - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

DIETARY FAT A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Dietary Fat: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83888-7 1. Dietary Fat-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on dietary fat. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON DIETARY FAT ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Dietary Fat.................................................................................... 7 E-Journals: PubMed Central ....................................................................................................... 64 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. NUTRITION AND DIETARY FAT ................................................................................ 113 Overview.................................................................................................................................... 113 Finding Nutrition Studies on Dietary Fat................................................................................. 113 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 117 CHAPTER 3. ALTERNATIVE MEDICINE AND DIETARY FAT .......................................................... 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 132 General References ..................................................................................................................... 156 CHAPTER 4. DISSERTATIONS ON DIETARY FAT ............................................................................ 157 Overview.................................................................................................................................... 157 Dissertations on Dietary Fat...................................................................................................... 157 Keeping Current ........................................................................................................................ 159 CHAPTER 5. CLINICAL TRIALS AND DIETARY FAT ....................................................................... 161 Overview.................................................................................................................................... 161 Recent Trials on Dietary Fat...................................................................................................... 161 Keeping Current on Clinical Trials ........................................................................................... 166 CHAPTER 6. PATENTS ON DIETARY FAT ....................................................................................... 169 Overview.................................................................................................................................... 169 Patents on Dietary Fat............................................................................................................... 169 Patent Applications on Dietary Fat ........................................................................................... 199 Keeping Current ........................................................................................................................ 233 CHAPTER 7. BOOKS ON DIETARY FAT ........................................................................................... 235 Overview.................................................................................................................................... 235 Book Summaries: Federal Agencies............................................................................................ 235 Book Summaries: Online Booksellers......................................................................................... 237 The National Library of Medicine Book Index ........................................................................... 244 Chapters on Dietary Fat............................................................................................................. 245 CHAPTER 8. MULTIMEDIA ON DIETARY FAT ................................................................................ 249 Overview.................................................................................................................................... 249 Video Recordings ....................................................................................................................... 249 CHAPTER 9. PERIODICALS AND NEWS ON DIETARY FAT ............................................................. 253 Overview.................................................................................................................................... 253 News Services and Press Releases.............................................................................................. 253 Newsletters on Dietary Fat ........................................................................................................ 256 Newsletter Articles .................................................................................................................... 257 Academic Periodicals covering Dietary Fat ............................................................................... 258 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 259 Overview.................................................................................................................................... 259 U.S. Pharmacopeia..................................................................................................................... 259 Commercial Databases ............................................................................................................... 261 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 265 Overview.................................................................................................................................... 265

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NIH Guidelines.......................................................................................................................... 265 NIH Databases........................................................................................................................... 267 Other Commercial Databases..................................................................................................... 270 APPENDIX B. PATIENT RESOURCES ............................................................................................... 271 Overview.................................................................................................................................... 271 Patient Guideline Sources.......................................................................................................... 271 Associations and Dietary Fat..................................................................................................... 278 Finding Associations.................................................................................................................. 279 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 281 Overview.................................................................................................................................... 281 Preparation................................................................................................................................. 281 Finding a Local Medical Library................................................................................................ 281 Medical Libraries in the U.S. and Canada ................................................................................. 281 ONLINE GLOSSARIES................................................................................................................ 287 Online Dictionary Directories ................................................................................................... 287 DIETARY FAT DICTIONARY.................................................................................................... 289 INDEX .............................................................................................................................................. 367

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with dietary fat is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about dietary fat, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to dietary fat, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on dietary fat. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to dietary fat, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on dietary fat. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON DIETARY FAT Overview In this chapter, we will show you how to locate peer-reviewed references and studies on dietary fat.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and dietary fat, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “dietary fat” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Comparison of High-and Low-Glycemic-Index Breakfast Cereals with Monounsaturated Fat in the Long-Term Dietary Management of Type 2 Diabetes Source: American Journal of Clinical Nutrition. 72(2): 439-449. August 2000. Contact: Available from American Journal of Clinical Nutrition. Production Office, 9650 Rockville Pike, Bethesda, MD 20814. (301) 530-7038. Fax (301) 571-8303. Website: www.ajcn.org. Summary: Results of research studies using 6 week intervals suggest that high carbohydrate diets are deleterious for people with type 2 diabetes. This article reports on a study undertaken to see whether long term replacement of monounsaturated fatty acids (MUFAs) with carbohydrate from breakfast cereals with either a high or a low glycemic index (GI) affected blood glucose (sugar) and lipids (fats) in subjects with type

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2 diabetes. Subjects with type 2 diabetes (n = 91) were randomly assigned to receive approximately 10 percent of energy from a low GI breakfast cereal, a high GI cereal, or oil or margarine containing MUFA for six months. Eating breakfast cereal was prohibited for the subjects in the MUFA group. The trial was completed by 72 subjects. The subjects who received cereals consumed approximately 10 percent more energy from carbohydrate than did the subjects in the MUFA group. Changes in glycated hemoglobin, body weight, and fasting cholesterol and triacylglycerol did not differ significantly among groups. HDL (high density lipoprotein) cholesterol increased by approximately 10 percent in the MUFA group compared with subjects who consumed either high or low GI cereals. During 8 hour metabolic profiles, mean plasma insulin was higher and mean free fatty acids were lower in the 2 cereal groups than in the MUFA group. The authors conclude that a 10 percent increase in carbohydrate intake associated with breakfast cereal consumption had no deleterious effects on glycemic control or blood lipids over 6 months in subjects with type 2 diabetes. The increase in plasma insulin and the reduction in free fatty acids associated with higher carbohydrate intake may reduce the rate of progression of diabetes. 6 figures. 5 tables. 51 references. •

Polyunsaturated Fatty Acids and Inflammatory Bowel Disease Source: American Journal of Clinical Nutrition. 71(1 Supplement): 339S-342S. January 2000. Contact: Available from American Journal of Clinical Nutrition. Production Office, 9650 Rockville Pike, Bethesda, MD 20814. (301) 530-7038. Fax (301) 571-8303. Website: www.ajcn.org. Summary: The rationale for supplementation with n-3 fatty acids to promote the health of the gastrointestinal (GI) tract lies in the antiinflammatory effects of these lipid (fat) compounds. The first evidence of the importance of dietary intake of n-3 polyunsaturated fatty acids was derived from epidemiological observations of the low incidence of inflammatory bowel disease (IBD) in Eskimos. This article briefly reviews the literature on the use of n-3 fatty acids in IBD (ulcerative colitis and Crohn disease), the results of which are controversial. The discrepancies between studies may reside in the different study designs used as well as in the various formulations and dosages used, some of which may lead to a high incidence of side effects. Choosing a formulation that lowers the incidence of side effects, selecting patients carefully, and paying strict attention to experimental design are critical when investigating further the therapeutic potential of these lipids in inflammatory bowel disease. 1 figure. 27 references.

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How to Cut Back on Saturated Fat Source: Diabetes Self-Management. 14(6): 44-46, 48-50. November-December 1997. Summary: This article focuses on ways to limit saturated fat and cholesterol intake. The authors point out that recent clinical studies have shown beneficial effects of a diet low in saturated fat and high in monounsaturated fat. Based on the data from these studies, this type of diet improves blood glucose control and lowers blood insulin levels in people with type 2 diabetes mellitus. Topics include triglycerides, fat versus carbohydrate, calculating fat intake, and food records and monitoring. According to the authors, clinical research and experiences since 1986 have shown that diets high in carbohydrates tend to increase plasma triglycerides, lower high density lipoprotein (HDL) cholesterol (the 'good' cholesterol), and have no favorable impact on low-density lipoprotein (LDL) cholesterol (the 'bad' cholesterol), especially in people with type 2

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diabetes. Accumulated scientific evidence now suggests that diets that contain up to 35 percent of total calories from fat, in which the composition of fat has been modified to reduce saturated fat and dietary cholesterol, appear to offer the best overall control of blood glucose and blood lipid metabolism in people who have diabetes. Nutrition experts recommend that people eat a variety of foods from each food group to ensure that their diet includes a variety of nutrients. The authors conclude that people should try decreasing the total carbohydrate and replacing it with monounsaturated fat if a meal plan high in carbohydrates routinely leads to high blood glucose. A table lists the calories, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, and cholesterol of various foods in the following categories: beef, pork, poultry, seafood, dairy, eggs, nuts, fats and oils, and other. A sample meal plan for one day, which provides about 2,000 calories, and a short list of reference materials are also included. 2 tables. (AA-M). •

Dietary Fat Intake as Risk Factor for the Development of Diabetes Source: Diabetes Care. 26(2): 302-307. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study that investigated the role of dietary factors in the development of type 2 diabetes. In the context of the Multinational MGSD Nutrition Study, three groups of subjects were studied: 204 subjects with recently diagnosed diabetes (RDM), 42 subjects with undiagnosed diabetes (UDM), and 55 subjects with impaired fasting glucose (IFG). Compared with control subjects, RDM more frequently had a family history of diabetes (49.0 versus 14.2 percent), exercised less, and more frequently had sedentary professions (47.5 versus 27.4 percent). Carbohydrates contributed less to their energy intake, whereas total fat and animal fat contributed more and the plant-to-animal fat ratio was lower. UDM more frequently had a family history of diabetes (38.1 percent versus 19.0 percent) and sedentary professions (58.5 percent versus 34.1 percent), carbohydrates contributed less to their energy intake, total fat and animal fat contributed more, and the plant-to-animal fat ratio was lower. IFG differed only in the prevalence of family history of diabetes (32.7 percent versus 16.4 percent). The authors conclude that these data support the view that increased animal fat intake is associated with the presence of diabetes. 1 figure. 2 tables. 36 references.

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Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men Source: Diabetes Care. 25(3): 417-424. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to examine dietary fat and meat intake in relation to risk of type 2 diabetes. The authors prospectively followed 42,504 male participants of the Health Professionals Follow-Up Study who were aged 40 to 75 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1986. Diet was assessed by a validated food frequency questionnaire and updated in 1990 and 1994. During 12 years of follow up, the authors ascertained 1,321 incident (new) cases of type 2 diabetes. Intakes of total fat and saturated fat were associated with a higher risk of type 2 diabetes. However, these associations disappeared after additional adjustment for body mass index (BMI). Intakes of oleic acid, trans fat, long chain n-3 fat, and alpha linolenic acid were not associated with diabetes risk after multivariate adjustment. Linoleic acid was associated with a lower risk of type 2 diabetes in men less than 65

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years of age and in men with a BMI less than 25 kilograms per meter squared, but not in older and obese men. Frequent consumption of processed meat was associated with a higher risk for type 2 diabetes. The authors conclude that total and saturated fat intake were associated with a higher risk of type 2 diabetes, but these associations were not independent of BMI. 4 tables. 50 references. •

Nonpharmacologic Treatment of Diabetic Dyslipidemia: Part I Source: Diabetes Spectrum. 6(5): 289-311. September/October 1993. Summary: This From Research to Practice section of Diabetes Spectrum focuses on the impact of nonpharmalogical treatment of the lipid abnormalities associated with noninsulin-dependent diabetes mellitus (NIDDM). One research article (with commentaries) discusses the prevention of NIDDM by diet and physical exercise as researched in the 6-year Malmo Feasibility Study. In addition, the section includes summaries of four studies (with commentaries) on the effects of changing dietary carbohydrate; carbohydrate and lipid metabolism; metabolic effects of substitution of complex carbohydrates for saturated fat in individuals with obesity and NIDDM; and the use of a high-carbohydrate, low-fat diet to lower plasma lipids and lipoproteins without producing hypertriglyceridemia. 2 figures. 2 tables. 127 references.

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Transplantation and Hyperlipidemia: What Is It and Why Should I Be Concerned? Source: Stadtlanders Lifetimes. Issue 3: 18-19. 2000. Contact: Available from Stadtlanders Lifetimes. Stadtlanders Pharmacy, 600 Penn Center Boulevard, Pittsburgh, PA 15235-5810. E-mail: [email protected]. Summary: This health newsletter article reviews hyperlipidemia (increased cholesterol or triglycerides in the blood) and its occurrence in transplant recipients. The author notes that organ preservation, surgical technique, postoperative care, and effective immunosuppressants are improving the life of the transplanted organ, but recipients are still succumbing to cardiovascular illness. Hyperlipidemia can occur early after the transplant procedure. Coronary artery disease (CAD), when the arteries supplying the heart become blocked with fatty substances, is the most worrisome effect of hyperlipidemia. In addition to some immunosuppressants, other medications that transplant recipients are often prescribed have been known to cause or worsen hyperlipidemia. The author stresses the importance of exercise as a way to combat high cholesterol levels in the blood. Exercise not only is beneficial on the lipid profile, but also reduces total body weight, strengthens muscle tone, and improves cardiovascular performance. Reducing saturated fat in the diet appears to have the most effect in the overall reduction of cholesterol. For patients whose hyperlipidemia is not controlled by at least three months of dietary therapy, treatment with medications should be considered. The author reviews the use of specific drugs (the 'statins') for the treatment of hypercholesterolemia and concerns about rhabdomyloysis (a breakdown of the skeletal muscle tissue, with the inability to clear the breakdown products through the kidney). The author concludes by encouraging readers to educate themselves and to work closely with their transplant team on the appropriate management of hyperlipidemia.

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Dietary Fat and Incidence of Type 2 Diabetes in Older Iowa Women Source: Diabetes Care. 24(9): 1528-1535. August 2001.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article describes a study, the Iowa Women's Health Study, that examined the associations between reported intakes of dietary fat and incident type 2 diabetes. The study population consisted of 35,988 women aged 55 to 69 years old who initially did not have diabetes. Diet was assessed with a food frequency questionnaire at baseline. The baseline questionnaire also obtained information on known or suspected risk factors for diabetes, including age, body mass index (BMI), waist to hip ratio (WHR), physical activity, alcohol consumption, and smoking history. The women were followed for 11 years, and 1,890 incident cases of diabetes occurred during this time. After adjusting for age, smoking, alcohol consumption, BMI, WHR, physical activity, demographic factors, and dietary magnesium and cereal fiber, diabetes incidence was negatively associated with dietary polyunsaturated fatty acids, vegetable fat, and trans fatty acids and positively associated with omega-3 fatty acids, cholesterol, and the Keys score. After simultaneous adjustment for other dietary fat, only vegetable fat remained clearly related to diabetes risk. Relative risks across quintiles of vegetable fat intake were 1.00, 0.90, 0.87, 0.84, and 0.82. Diabetes risk was also inversely related to substituting polyunsaturated fatty acids for saturated fatty acids and positively correlated to the Keys dietary score. The article concludes that the data support an inverse relationship between incident type 2 diabetes and vegetable fat. In addition, substituting polyunsaturated fatty acids for saturated fatty acids appeared to reduce the rate of diabetes. 3 tables. 48 references. (AA-M).

Federally Funded Research on Dietary Fat The U.S. Government supports a variety of research studies relating to dietary fat. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to dietary fat. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore dietary fat. The following is typical of the type of information found when searching the CRISP database for dietary fat: •

Project Title: ACCURATE NONINVASIVE TEST OF STEATORRHEA IN INFANTS Principal Investigator & Institution: Janghorbani, Morteza; Biochemanalysis Corporation 2201 W Campbell Park Dr Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2005

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Summary: (provided by the applicant): The long-term objectives of this proposed project are to develop a "Test Kit" for quantitative assessment of steatorrhea in infants without the need for control of dietary fat intake and quantitative collections of stools for several days as is the case with the current "Gold Standard," viz, the 72-hour fecal fat method. Our proposed "Test Kit" is based on administering a feeding of infant formula containing a suitably labeled 13C-triglyceride (TG), a trace amount of the nonabsorbable marker dysprosium chloride (DyC1-3) and the visual marker Brilliant Blue followed by laboratory analysis of Dy and 13C-Excess in one or more sample(s) of stool containing the visual marker. The research conducted during Phase-I of this grant has led to the selection of 1,3-(13C-2) dipalmitoyl, 2-lauryl glycerol (P*LP*) as the most suitable TG* for applications in infants. During Phase II of the project, we propose to conduct clinical protocols with cystic fibrosis and healthy infants in order to: (1) define the parameters of the expected linear correlation between fecal excretion of P*LP* and fecal fat, (2) demonstrate the significance of this novel method in medical management of infants with steatorrhea, and (3) obtain research data necessary for the manufacture of a safe and noninvasive "Test Kit" for accurate assessment of steatorrhea in infants. The "Test Kit" has widespread applications in clinical management of infants with a wide range of disorders leading to steatorrhea. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADIPOSITY SIGNALS IN DIETARY OBESITY Principal Investigator & Institution: Woods, Stephen C.; Director, Obestiy Research Center; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 31-DEC-2005 Summary: Obesity and its associated pathologies are a major health problem throughout the world. And in spite of years of focused research, two conclusions are inescapable. The first is that the health-care community has only ineffective treatments to offer, relegating obese individuals and their societies to a lifetime of psychological, medical and economic hardship. The second and more sobering is that the incidence of obesity continues to rise, the rate being accelerated in countries as they become economically more self-sufficient. One factor thought to contribute to this is a high level of dietary fat intake. The goal of Project 2, like that of the entire Program Project, is to begin defining the mechanisms underlying in a rigorous and systematic way the changes that occur in the body when a diet high in fat is consumed. The overall goal of Project 2 is to evaluate several hypotheses concerning the adiposity-related negative feedback signals that are critical in the regulatory process that governs adiposity. Specifically, I hypothesize that chronic consumption of a high-fat diet reduces the ability of the adiposity signals, insulin and leptin, to cross the blood-brain barrier, such that the brain receives an inaccurate (in fact, relatively reduced) signal regarding body fat content. I further hypothesize that chronic consumption of a high-fat diet lowers the sensitivity of the brain to leptin and insulin. There are three specific aims. 1) To evaluate the hypothesis that chronic consumption of high-fat diet reduces the sensitivity of the brain to intraventricularly (ivt) administered insulin and leptin. 2) To evaluate the hypothesis that chronic consumption of a high-fat diet reduces the insulin- and leptin-induced augmentation of cholecystokinin (CCK)-induced reduces of single-meal size. 3) To evaluate the hypothesis that the transport of insulin and leptin form plasma into the central nervous system (CNS) is compromised in animals fed a high-fat diet chronically. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANDROGEN PATHWAY FACTORS AND PROSTATE CANCER Principal Investigator & Institution: Witte, John S.; Professor; Epidemiology and Biostatistics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Prostate cancer is a common, but complex disease. Risk factors for this disease are not yet fully understood, but may involve both genetic and environmental influences. These factors may act alone, or in combination, to increase risk of prostate cancer. Some of the most promising potential risk factors are those involved with androgen metabolism, which drives prostate cell growth and differentiation. Therefore, in the following specific aims we propose an epidemiologic study of the relation between prostate cancer and two factors that may affect the androgen metabolism pathway: candidate genes and dietary fat. Specific Aim 1. Our first aim is to investigate the impact of novel or little studied polymorphisms in the following ten androgen pathway candidate genes on prostate cancer risk: 1) CYP3A4; 2) 5a-reductase II; 3) CYP1 7; 4) the Androgen Receptor; 5) Kallikrein 3; 6) 3Betahydroxysteroid dehydrogenase II; 7) CYP1 la; 8) CYP19; 9) Insulin-like Growth Factor-I; and 10) CYP1B1 Specific Aim 2. This aim will expand our consideration of the androgen pathway by investigating the relation between prostate cancer risk and consumption of polyunsaturated dietary fat, and the polyunsaturated fatty acids linoleic acid and alphalinoleic acid. Specific Aim 3. Our third aim is to synthesize the information on candidate genes and dietary fats studied here by looking at their joint and interactive effects on prostate cancer risk. We will use both a conventional analysis, and a hierarchical modeling approach, which will attempt to improve our estimates of risk by incorporating into the analysis biologic information about the affect of these candidate genes and dietary fat on the androgen pathway. To fulfill these specific aims, we will use existing information from a sibling-based study of 455 cases and 488 controls Our comprehensive evaluation of androgen pathway factors should help clarify the impact of these genetic and dietary factors on prostate cancer. Ultimately, findings from such work will help lead to individualized screening that expressly reflects a man's risk of prostate cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MARKERS

BARRETTS

ESOPHAGUS--DIET

INTERVENTION/INTERMED

Principal Investigator & Institution: Reid, Brian J.; Associate Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 21-SEP-1995; Project End 31-AUG-2002 Summary: Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the esophagus is replaced by a metaplastic columnar epithelium. It develops as a complication of chronic gastroesophageal reflux disease and predisposes to the development of adenocarcinomas of the esophagus and gastric cardia. Barrett's associated adenocarcinomas are the most rapidly increasing cancers in the United States, but they are rarely discovered in time for Cure. Intensive endoscopic biopsy surveillance of patients with Barrett's esophagus can detect early, potentially curable Barrett's adenocarcinomas, but such surveillance is costly and time consuming. Dietary recommendations including a low-fat diet and weight reduction are an accepted part of standard medical therapy for patients with gastroesophageal reflux and Barrett's esophagus, but the efficacy of this diet in reversing intermediate endpoints of neoplastic progression in Barrett's esophagus and decreasing symptoms and mucosal damage

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associated with reflux has never been established in a randomized, clinical trial. The specific aims of this application for a cooperative agreement are to determine whether a dietary intervention to reduce the intake of dietary fat, increase the intake of fruits and vegetables, and reduce weight can l) reverse intermediate endpoints of neoplastic progression (increased G1 and S phase fractions) in Barrett's esophagus, and 2) lead to partial regression of premalignant metaplasia (as evidenced by the development of islands of normal squamous epithelium in the metaplastic columnar epithelium). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOBEHAVIORAL HYPERPHAGIA

MECHANISMS

OF

HIGH-FAT

DIET

Principal Investigator & Institution: Warwick, Zoe S.; Associate Professor; Psychology; University of Maryland Balt Co Campus Baltimore, Md 21250 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: The reduction of fat intake by Americans has been identified as a major public health goal, since excessive consumption of fat has been linked to numerous negative health consequences including obesity, cardiovascular disease, and some types of cancer. Thus, there is compelling need to identify the behavioral mechanisms and dietary attributes which foster overconsumption (hyperphagia) of high-fat foods. The proposed studies will utilize an animal model to determine the independent and interactive contributions to oral sensations (palatability), caloric density, and the unique postingestive effects of dietary fat to the control of intake. This will be accomplished by systematically manipulating each of these variables while holding the others constant, and examining the impact on both short-term measures of ingestive behavior (meal size and postprandial satiety) and long-term (16 day) intake relative to controls fed a highcarbohydrate, low-fat diet. The use of liquid diets allows easy manipulations of dietary attributes, and also permits isolation of oral and postingestive influences on intake via the techniques of sham feeding and intragastric feeding, respectively. These methods will eliminate the confounding of dietary variables that has been unavoidable in traditional oral-feeding studies, and thus will enable an unbiased assessment of the relationship of each variable to intake. Humans exhibit individual differences in the accuracy with which caloric intake is regulated when consuming a high-fat diet, as do rats. An additional goal is to determine whether short-term measures of ingestive behavior are useful predictors of individual differences in the magnitude of high-fat diet hyperphagia. To determine whether discrete measures correlate with individual differences in the magnitude of high-diet hyperphagia, taste responsivity to fat (via sham-feeding), meal size, and postprandial satiety (via a preloading paradigm) will be obtained prior to lad lib consumption of a high-fat diet. Identification of a behavioral marker(s) for susceptibility to overeating, such as abnormally large meal size or reduced sensitivity to the satiating effect of fat, would be clinically valuable if a similar predictive relationship were then found in humans. Together, results from these studies will provide a greater understanding of how and why high-fat diets promote excessive intake and weight gain by focusing on both the specific dietary attributes that elicit overeating, and the behavioral mechanisms through which the hyperphagia is expressed. An increased understanding of the underlying determinants of high-fat diet hyperphagia has the potential to inform and positively impact clinical and public health strategies aimed at promoting a healthier level of fat intake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANDIDATE SELECTION QTL

GENE

ANALYSIS

FOR

11

MACRONUTRIENT

Principal Investigator & Institution: Smith-Richards, Brenda; Lsu Pennington Biomedical Research Ctr 6400 Perkins Rd Baton Rouge, La 70808 Timing: Fiscal Year 2003; Project Start 01-AUG-1999; Project End 31-JUL-2007 Summary: (provided by applicant): This application is a direct continuation of our previous grant directed at the genetic mapping of QTL controlling macronutrient selection in the C67BL/6J and CAST/Ei mouse inbred strains which differ markedly in their self-selected intake of macronutrient diets. A genome-wide scan revealed significant linkage for traits representing self-selected fat and carbohydrate intake on chromosome 6, 8, 17, 18 and X. Loci on chromosome 17 and 18 were linked also to total energy intake when body weight was used as a covariate. These are the first QTL for food preference or total energy intake that have been mapped in the mouse. The overall goal of the current proposal is to identify candidate genes underlying Mnif1, a quantitative trait locus (QTL) for dietary fat intake located on chromosome 8, and Mnic1 on chromosome 17 for carbohydrate and kilocalorie intake. In Aim 1, we will isolate and narrow the Mnif1 and Mnic1 intervals to a size suitable for the positional candidate approach, by developing B6.CAST congenic and subcongenic lines. In Aim 2, gene expression microarrays will be used to identify candidate genes. The probes for the microarrays will consist of cDNA from tissues of the recipient strain (B6) and the interval-specific subcongenic strains (B6.CAST) developed in our laboratory, mRNA will be harvested from tissues important in the regulation of food intake phenotypes, i.e, hypothalamus, solitary tract nucleus/area postrema, liver, stomach, small intestine, pancreas, adipocyte, muscle. First, a genome-wide gene expression screen will be performed using a mouse oligonucleotide array (16,463 genes from UniGene) now ready and available from the PBRC Genomics Core. Thus we will characterize transcriptional differences that occur upstream or downstream from effects of genes within the QTL. These data will provide an entry point for modelling the process by which these feeding behaviors are controlled, and for identifying the most promising tissues to profile with the QTL-specific arrays. Next, custom arrays will be designed for the purpose of performing comprehensive analyses of the transcriptional activity of all mouse and human genes present in the subcongenic intervals for the QTL controlling fat intake on Chr 8 (Mnif1) and carbohydrate intake on Chr 17 (Mnic1). Knowledge of the biology of the feeding traits and analysis of differentially expressed genes within and outside of the QTL will help us reduce the number of candidates to a very few and select those that deserve further investigation for a functional role in determining the phenotype. Candidate gene identification will enhance our understanding of the regulation of food intake. Finding genes regulating macronutrient intake in mice will help us to understand the contribution of genetic versus environmental factors affecting food preferences in humans. This should lead to valuable insights into obesity and diabetes, and new approaches for modifying macronutrient selection that could be useful in controlling weight gain or promoting weight loss. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARBOHYDRATE APPETITE, FAT APPETITE AND OBESITY Principal Investigator & Institution: Sclafani, Anthony; Distinguished Professor; Psychology; Brooklyn College 2900 Bedford Ave New York, Ny 11210 Timing: Fiscal Year 2001; Project Start 01-JUL-1984; Project End 30-JUN-2006

12

Dietary Fat

Summary: This project will investigate the psychobiological factors that influence the preference for and consumption of carbohydrate-rich and fat-rich foods. There has been considerable concern that diets high in simple carbohydrates, and even more so high in fat, promote human disease and obesity. Laboratory research has documented that highsugar and high- fat foods promote overeating, overweight, and obesity in animals. However, the psychobiological mechanisms responsible for these effects remain incompletely understood. Of particular importance are the determinants of food choice: why do animals (including humans) select sugar- and fat-rich foods when many food options are available? The orosensory properties (flavor) of high-sugar and high-fat foods are clearly attractive to animals. It is now known that the postingestive actions of these nutrients significantly enhance carbohydrate and fat appetites. Until recently, postingestive nutrient actions were considered to be exclusively inhibitory (satiating) in nature, but recent findings demonstrate that nutrients have positive (reinforcing) postingestive consequences that influence food choice and consumption by conditioning flavor preferences and acceptance. The specific aims of this project are to (1) Investigate the relationship between nutrient reinforcement and satiety in learned food preferences. (2) Determine the effects of deprivation state on conditioned flavor preference and acceptance. (3) Reveal the effects of nutrient reinforcement on consummatory, appetitive and instrumental behaviors. (4) Evaluate the unconditioned stimuli in nutrientconditioned flavor preferences. (5) Investigate the central neural mediation of flavornutrient preference conditioning. This research involves the fields of psychobiology, neuroscience, nutrition, and gastrointestinal physiology. It will advance our basic knowledge of the psychobiology of carbohydrate and fat appetite and the development of food preferences. The findings may provide practical benefits for current attempts to alter dietary fat and carbohydrate intake and control adiposity in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD36 AND INTESTINAL FAT ABSORPTION Principal Investigator & Institution: Abumrad, Nada A.; Professor; Physiology and Biophysics; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): In 1993 we identified the membrane protein CD36 as a transporter for long-chain fatty acids (FA). A wealth of evidence supporting such a role was subsequently obtained by us and by others. Recent work with animal models of CD36 deficiency or overexpression documented that, in vivo, CD36 mediates greater than 60 percent of FA transport in key tissues. In humans, CD36 deficiency was linked to defects of myocardial FA uptake and to hypertrophic cardiomyopathy. This proposal is based on the hypothesis that CD36 plays an important role in lipid absorption in the small intestine, based on several pieces of evidence. First, CD36 has been documented to facilitate FA uptake and esterification in key tissues where it is highly expressed and its expression levels in the intestine are very high. Second, in the small intestine CD36 is highest in the jejunum and is localized apically in the upper two thirds of microvilli enterocytes, where most FA are absorbed. Third, our preliminary data indicate that CD36 null mice exhibit a delayed and low response of plasma triglycerides (TG) after an oral fat load. Our aims are to define the defect in absorption and chylomicron production in CD36 null mice. The importance of CD36 to fat absorption and energy metabolism overall will be assessed from examining susceptibility of CD36 null and wild type mice, where intestinal CD36 will be specifically inhibited, to high fat dietinduced obesity. Other studies with CD36 null mice and with Caco 2 cells infected with an adenoviral construct containing CD26, will explore the role of Cd36 in directing the

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FA to chylomicron production and in determining polarity of FA metabolism in the enterocyte. The work will contribute to the understanding of intestinal FA absorption and of FA metabolism in enterocytes. It may help design new approaches aimed at preventing the obesity induced by consumption of high dietary fat. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CNS MECHANSIMS IN DIETARY OBESITY Principal Investigator & Institution: Seeley, Randy J.; Professor; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: This project is aimed at elucidating CNS mechanisms that underlie the increase in body adipose mass that is associated with consuming a diet high in dietary fat. CNS systems involved in food intake can be conceptually divided into two categories, anabolic and catabolic. Anabolic effectors are those than when activated, elicit increased food intake, decreased energy expenditure, and consequently increased stored energy in the form of adipose tissue mass. Catabolic effector pathways do just the opposite: decrease food intake, increase energy expenditure and result in decreased adipose tissue mass. A critical part of this feedback model is that hormones responsive to the level of adiposity inhibit anabolic pathways while activating catabolic pathways, and that the balance between these pathways that ultimately the animal's ingestive behavior and defended level of adiposity. The guiding hypothesis underlying this proposal is that high-fat diets increase activity in anabolic effector pathways and/or decrease activity in catabolic effector pathways and thereby produce and maintain a long-lasting and non-compensated mismatch between caloric intake and caloric expenditure. The dietary model and 5 basic groups for individual experiments we propose to use a variety of single and double-labeling techniques in addition to CNS application of peptides to accomplish 3 specific aims: 1) To evaluate the hypothesis that the high-fat diet alters the activity and/or signaling of arcuate nucleus neurons sensitive to the adiposity signals, insulin and leptin. 2) To evaluate the hypothesis that maintenance on a high-fat diet decreases catabolic activity and/or signaling in the paraventricular nucleus. 3) To evaluate the hypothesis that maintenance on a high-fat diet alters sensitivity to a variety of hypothalamic peptides when administered into the CNS. Understanding how brain mechanisms associated with the normal regulation of food intake and body weight are altered by high-fat diets is a critical component to understanding how high-fat diets promote obesity. Information from the execution of these experiments will provide insight into these mechanisms and point to potential novel therapeutic strategies particularly when combined with information from the other 2 projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMMUNITY-SITE CORONARY RISK CONTROL IN BLACK FAMILIES Principal Investigator & Institution: Becker, Diane M.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: This study tests the effectiveness of Neighborhood Health Worker/Nurse Case Management compared with usual care (referral to usual primary care source) for the management of coronary heart disease risk factors in African American siblings of persons with premature coronary disease. Index patients with documented coronary

14

Dietary Fat

disease prior to 60 years of age will be recruited from 7 Baltimore hospitals to identify 480 siblings to be screened to identify those with a criterion risk factor (LDL- cholesterol greater than 130 mg/dl, blood pressure greater than 140/90 mmHg, and/or cigarette smoking) (n=433). Eligible siblings are those between 30 and 60 years of age with no known coronary disease. Siblings with criterion risk factors after screening will be randomly assigned by family to receive care in the community by a case management team consisting of a Neighborhood Health Worked guided by a nurse and cardiologist, or to receive usual care. Siblings will be followed one year after screening to determine the proportion in each group who meet goal levels of blood pressure, LDL-cholesterol, dietary fat, physical activity, and smoking cessation. The study builds on prior work in both the African American community and in siblings that shows that 1.) nurse managed care produces more successful risk reduction, 2.) African Americans accept care in the community and from Neighborhood Health Workers, and 3.) sociocultural models of care are more likely to be successful in high risk African American families. The goal is to increase the proportion of high risk siblings who achieve goals based on national guidelines. This is one of the first studies to empirically examine a combination of community intervention for multiple risk factor reduction using indigenous workers and approaches which address the needs of individuals with a documented family history of premature coronary heart disease. Analysis will include the test of proportions achieving goals and multiple logistic regression analysis predicting favorable change, adjusted for intra-family clustering of baseline risk factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTERIZED POPULATION PROGRAMS FOR THREE CANCER RISKS Principal Investigator & Institution: Velicer, Wayne F.; Co-Director; Cancer Prevention Research Ctr; University of Rhode Island 70 Lower College Road, Suite 2 Kingston, Ri 028810811 Timing: Fiscal Year 2001; Project Start 26-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The specific aims of this research project are (1) to replicate one of the most effective approaches to behavioral intervention, a series of expert system interventions, for both smoking cessation and reduction of dietary fat on a national sample; (2) to extend the intervention to the reduction of sedentary life style; (3) to develop and assess the effectiveness of an innovative automated counseling intervention, the TLC telecommunications system, applied to the same 3 behavioral risk factors; (4) to compare the effectiveness of the current modular expert system approach with an integrated expert system intervention, and (5) to determine the costeffectiveness of each of the 3 interventions. All subjects will be at risk for all 3 risk factors and all interventions would intervene on all 3 risk factors simultaneously. The modular expert system intervention involves 3 assessments, each followed by 3 separate feedback reports at 6-month intervals for each of the risk factors. The telecommunications system involves briefer assessments on each risk factor and counseling luring regular telephone contacts over a 12-month period. The integrated expert system intervention involves a single assessment on 3 occasions of all 3 risk factors followed by intervention on all 3 risk factors simultaneously in an attempt to increase efficiency and capitalize on the covariance between the behaviors. All 3 interventions are based on the Transtheoretical Model. The national sample would be 1600 subjects recruited throughout the continental United States using random digit dial telephone methodology. All interventions are designed to impact on a total population and a proactive recruitment procedure will be employed to recruit more than 75 percent

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of the eligible sample. The design is a 4-group (Control, Modular Expert System intervention, Telecommunications Intervention, Integrated Expert System Intervention) x 3 occasions (0, 12, and 24 months). Each behavioral risk factor will be intervened upon for 12 months and the 3 risk factors will be related simultaneously. The 3 interventions evaluated in this project have the potential to be easily disseminated at low costs to entire populations of at-risk individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--LIPIDS AND CHRONIC DISEASES Principal Investigator & Institution: Krauss, Ronald M.; Senior Medical Scientist; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Overall Objectives of the Lipids and Chronic Diseases Research Core: High intakes of lipids and calories are associated with increased incidence and severity of chronic diseases including diabetes, obesity, certain cancers, and cardiovascular diseases (CVD). As a consequence of high intakes of fat, lipid metabolism is altered and contributes to the initiation and development of disease processes. The disease process in turn alters metabolism further contributing to additional complications. One of the most prevalent risk factors and targets of therapy for these diseases is dyslipidemias, which are known to be affected by diet. Minority populations have disproportionately high incidences and morbidities of all chronic diseases and specifically prostate cancer (Powell and Meyskens 2001), diabetes (Kamel, Rodriguez-Saldana et al. 1999), asthma (Strunk, Ford et al. 2002), obesity (including childhood obesity (Crawford, Story et al. 2001), and cardiovascular diseases (CVD). Observations from the largest survey of dietary habits and health status in the U.S., the Third National Health and Nutrition Examination Survey (NHANES), have established that older black and Mexican American women and black men were at greatest risk for CVD (Winkleby, Kraemer et al. 1998; Sundquist, Winkleby et al. 2001), paralleling the heightened risk of CVD among younger ethnic minority populations (Winkleby, Robinson et al. 1999). Multiple CVD risk factors, including plasma lipids as well as dietary fat, obesity, hypertension, and diabetes, contribute to these ethnic differences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COUNSELING FOR OVERWEIGHT WOMEN FOR DIET AND ACTIVITY Principal Investigator & Institution: Patrick, Kevin M.; Adjunct Professor; Student Health Services; San Diego State University 5250 Campanile Dr San Diego, Ca 92182 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: Improved physical activity (PA) and dietary behaviors show great promise to reduce risk of cancers, CVD, NIDDM and other diseases. Improvements in PA and nutrition are particularly important for the overweight, a condition now affecting more than 50 percent of Americans. There are few effective programs for treating overweight in primary care. In this project we will evaluate an integrated clinical and home- based intervention to improve PA and dietary behaviors in overweight (BMI 25-29.9) women. PACE+ has three integrated components, a computer assessment and action planner, provider counseling; and 12 months of extended phone and mail contact. Pilot study results (n=173) demonstrate that PACE+ shows substantial promise in improving dietary and PA behaviors We will recruit 360 overweight women age 18 to 45 seen in 4 healthcare settings. Subjects will be randomly assigned to PACE+ or a usual care,

16

Dietary Fat

delayed treatment control comparison condition. PACE+ targets three primary and three secondary behaviors: Primary: a) dietary quality (fruits and vegetables, vitamin C, carotenoids, and fiber); b) total dietary fat as a percent of energy consumed; and c) energy expenditure from moderate and vigorous physical activity during leisure-time. Secondary: a) recreational media use; b) overeating; c) saturated fat as percent of energy consumed. PACE+ also assesses stage of change and psychosocial mediators of behavior change. The PACE+ computer program guides patients to select one dietary and one PA target behavior for which they develop action or maintenance plans to discuss with the provider. The provider endorses or modifies the action plan and encourages participation in the extended phone and mail intervention. Phone counseling, mail and print materials guide the patient to use cognitive and behavioral skills to make changes in target behaviors. At six months subjects are reassessed over the phone and then continue to receive stage-appropriate intervention to address their new diet and PA goals. Primary outcomes ((a) a combined measure of energy expended in moderate and vigorous physical activity during leisure; ) an index of dietary quality encompassing increased fruits and vegetables and nutrient indicators of these foods; and (c) total dietary fat as a percent of energy consumed) will be assessed at baseline and 12 months with 7-day PA recall and food frequency questionnaires. Secondary outcomes and mediators of behavior change will be measured at baseline, 6, 12 and 24 months. Secondary outcomes include objective and self-report measures of PA and recreational media use and self-reported dietary behaviors (overeating; saturated fat intake as a percent of total energy consumed), BMI, skinfolds, waist circumference, psychosocial mediators of change. Exploratory assessment of plasma carotenoids and 24-hour dietary recall will be performed on a sub-sample of subjects to validate self report measures. The PACE+ intervention is particularly innovative in that three components - computer, primary care provider counseling, and an extended home-based intervention - are unified through a common theoretical framework. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DECREASING PREADOLESCENT

WEIGHT

GAIN

IN

AFRICAN-AMERICAN

Principal Investigator & Institution: Story, Mary; Professor; Epidemiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-MAY-2002 Summary: The increased prevalence of many of the health problems of African American women has been linked to the high prevalence of obesity. Of great concern, the prevalence of obesity has been increasing among African American women with a similar pattern in African American girls. Since weight reduction weight is difficult to achieve in adulthood, there is an urgent need for prevention approaches geared towards children. This proposal describes a two-phase plan to develop and evaluate a community-based intervention that promotes healthy dietary practices and increased physical activity among at risk or overweight 8-10 year-old African American girls living in low- income neighborhoods in the Twin Cities of Minneapolis and St Paul, Minnesota. A randomized clinical trial design will be used with 300 African American girls; 150 will be individually randomized to the intervention group and 150 to the control group. The intervention program will take place after school, two afternoons a week in neighborhood community centers and will be based on social cognitive theory, incorporating a youth development, resiliency-based approach. Community involvement through the establishment of a Community Advisory Council will provide input into all aspects of the study. The intervention focuses on activities designed to

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model and teach skills to prevent obesity through regular physical activity and healthy eating and a family component designed to reinforce and support these behaviors. An effective and innovative culturally- appropriate intervention will be developed through formative assessment with girls, parents, community leaders and youth workers in the targeted communities. In Phase I, a 12-week pilot-test will be conducted with 50 girls; 25 randomized to the intervention and 25 to the control group. In Phase II, the two-year intervention will be conducted in five community centers, twice a week for 11 months. Main outcome measures will be body mass index (BMI) and percent body fat (percent BF). The major hypothesis is that at the end of the full-scale study, girls in the intervention group, relative to girls in the control group, will have significantly lower BMI and percent BF after adjustment for baseline values. Secondary outcomes include physical activity level, total energy intake, percent intake from dietary fat, child and parent psychosocial factors related to diet and physical activity, blood cholesterol and blood pressure. Process measures will assess program implementation including measures of exposure, participation, compliance, receptivity, and fidelity of implementation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIET AND GENETIC RISKS FOR PROSTATE CANCER Principal Investigator & Institution: Neuhouser, Marian L.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 23-JUN-2003; Project End 30-APR-2006 Summary: (provided by applicant): Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths among American men. Prostate cancer etiology remains elusive but there is growing evidence that dietary patterns are associated with prostate carcinogenesis. The most consistent dietary finding is that diets high in fat or high-fat foods increase risk and there is increasing evidence that compounds found in vegetables (e.g., lycopene, glucosinolates) decrease risk. However, results are not consistent across studies and there is no scientific consensus for specific dietary recommendations to reduce prostate cancer risk. Non-dietary factors associated with risk include age, race and family history. These and other risk factors may interact with dietary components and alter the prooxidant-antioxidant balance in the prostate. This proposal is for a comprehensive investigation into the associations of dietary fat, fruit and vegetable intakes and polymorphisms in genes that encode oxidative stress regulatory enzymes with the risk of prostate cancer. Our hypothesis is that dietary and other factors that increase oxidative stress (e.g., dietary fat, smoking) are associated with increased risk of prostate cancer; dietary factors that decrease oxidative stress are associated with decreased risk of prostate cancer; and the magnitude of these risks will vary by cancer susceptibility genetic profile. We will test whether polymorphisms in genes whose products affect tissue responses to oxidative stress influence prostate cancer risk, and whether there are interactions of these polymorphisms with dietary factors related to oxidative stress. Our study sample is the 12,025 male participants in CARET (The Beta-Carotene and Retinol Efficacy Trial). To date, there are 718 confirmed cases of primary prostatic carcinoma. This proposed study will provide important information about prostate cancer etiology and suggest new strategies for prevention and control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Dietary Fat

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Project Title: DIET AND PHYSICAL ACTIVITY INTERACTIONS IN OBESITY Principal Investigator & Institution: Hill, James O.; Professor; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-MAY-1990; Project End 31-JUL-2003 Summary: The current epidemic of obesity has occurred despite the existence of a body weight regulatory system which, for most of mankind's history, has matched energy intake with energy expenditure sufficiently to avoid obesity. This suggests that the primary cause of the current obesity epidemic is not genetic, but may be due to an environment in which the energy balance regulatory system cannot function with sufficient precision to keep the population lean. In this application, we propose research aimed at understanding how factors in the environment, namely high fat/energy dense diets and physical inactivity, can promote obesity by affecting the precision of regulation of energy and fat balance. It is our intent to identify dietary and physical activity patterns that are associated with increased precision of energy balance regulation and which can prevent development of obesity. Laboratory data suggest that high fat diets promote obesity by increasing the probability of overconsumption of total energy. Our first aim is to systematically examine the relationship between dietary fat and energy intake across a range of diet compositions in sedentary subjects. While this has been done for diets with extreme variation in dietary fat (i.e., less than or equal to 20 percent vs greater than or equal to 40-60 percent) it has not been done for dietary fat content within the range of usual consumption of U.S. adults (i.e. 20-40 percent fat diets). We hypothesize that this relationship will not be linear and that there will be a threshold level or a range of dietary fat associated with a low probability of increased energy intake and positive energy balance. This information will be useful in developing dietary guidelines for obesity prevention. Our second aim is to determine how level of physical activity interacts with dietary fat content to affect the likelihood of developing positive energy balance. We hypothesize that the optimum level of dietary fat to minimize the probability of positive energy balance will depend on level of physical activity and the optimum level of physical activity to minimize the likelihood of positive energy balance will vary with dietary fat content. This work will be among the first to study the interaction of dietary and physical activity patterns in promotion and prevention of obesity. The results will help identify the changes required in current dietary and physical activity patterns if we are going to be successful in preventing the development of obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIET, COLON CANCER, AND CANCER COMMUNICATIONS Principal Investigator & Institution: Abouta, Jessie S.; Nutrition; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 10-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): This application describes a career development/transition plan for Jessie A. Satia, PhD, MPH, a newly appointed Assistant Professor in the Department of Nutrition at the University of North Carolina, Chapel Hill. The candidate's overall career goal is to establish an interdisciplinary research career combining her background in epidemiology, nutrition, and laboratory sciences to conduct methodologic, observational, and intervention studies of diet and human cancers. In particular, she would like to conduct studies to identify risk factors for cancer and design appropriate interventions for prevention and control in minority and underserved populations. The candidate proposes a career development plan that

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includes: teaching and mentoring students; submitting research manuscripts and pilot project proposals; and a research plan (75% of her effort) with two proposed projects. Project 1 titled "Cancer Communications among African American Adolescents" aims to collect information necessary to design diet-related cancer prevention messages for African American adolescents; and evaluate the effectiveness of messages framed in different ways on knowledge, attitudes, beliefs, and intentions to improve diet in this population. Qualitative methods will be used to collect information on various factors that affect dietary behavior among African American adolescents (14 to 16 years) in Durham, NC. This information will then be used to design messages focused on lowering dietary fat intake in this population that will be delivered via the Internet. Participants will be randomized into four groups based on Prospect theory and message framing, and will complete pre- and post-tests and cognitive interviews to assess the short-term impact of the framed messages. Project 2, "Diet and Colon Cancer in African Americans and Whites in North Carolina" describes proposed analyses using previously collected data from a study of 654 colon cancer cases (40-80 years) and 1067 populationbased controls, with equal numbers of African Americans and whites, in a 33-county area of North Carolina. The specific aims of the analyses proposed here are to examine effects of dietary factors (e.g., fat, fruits, vegetables, antioxidants, fiber, alcohol, and total calories) and food intake patterns (meal frequency and snacking timing) on colon cancer risk. Potential future research opportunities using biological specimens from this study are described. The long-term success of cancer research efforts rests, in part, on building the career of talented young faculty. Obtaining this award will greatly broaden and strengthen the candidate's focus on cancer prevention and control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIET, IMMUNE MODULATION, AND ASTHMA IN EARLY LIFE Principal Investigator & Institution: Weiss, Scott T.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: Asthma is the most common chronic disease of childhood in the developed world, affecting about 10 million U.S. children under the age of sixteen. Asthma prevalence in Western industrialized countries is increasing at an alarming rate, and this increase is coincident with an increase in type I hypersensitivity (allergy). Eighty percent of childhood asthmatics exhibit hypersensitivity to indoor aeroallergens. Maternal diet represents an important exposure that has significant potential to modify immune function and, hence, the development of allergy. To study the evolution of the asthmatic immune response, focusing on the cellular response to allergens and foods, this application proposes a collaborative study involving pulmonary and dietary epidemiologists (Drs. Weiss, Colditz, and Gold), experts in lipid biochemistry (Dr. Sacks) and immunologists specializing in the role of T- and B-cells in the asthmatic response (Drs. Finn and Perkins). The application proposes to utilize a prospective longitudinal cohort study of children of asthmatic mothers to examine the role of maternal dietary fat intake (N-3 polyunsaturated fat) in the development of (1) nonspecific and specific cellular immune responses by age 2-3; (2) asthma/wheeze, atopic dermatitis, food allergy, and allergic rhinitis by age 3. In a subset of 50 five year old children with asthmatic mothers, 25 with high and 25 with low N-3 fatty acid intake during pregnancy, studies will assess lymphocyte proliferation and cytokine production (IL-4, IL-5, and interferon-gamma [IFN-gamma]) to nonspecific (PHA) and representative specific antigenic stimulation: beta-lactoglobin (food), cockroach (Bla g2) and dust mite (Der fI) (indoor allergen). Additional potentially influential host and

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Dietary Fat

environmental factors to be examined include: parental asthma history, maternal age, perinatal history, acute lower respiratory illness history, day care, environmental tobacco smoke, birthweight, head circumference, sex, and race. The application proposes to test the following hypotheses: 1. At birth, maternal dietary N-3 fatty acid levels assessed in the second and third trimester of pregnancy with a semiquantitative food frequency questionnaire will be correlated with N-3 fatty acid levels in cord blood. 2. At birth, infants with high cord blood levels of N-3 fatty acids will have reduced lymphocyte proliferative responses to cockroach, dust mite (indoor allergen), and betalactoglobin and reduced levels of inflammatory cytokines (IL-4, IL-5) and increased levels of interferon-gamma. 3. High cord blood levels of N-3 fatty acids and reduced lymphoproliferative responses to cockroach, dust mite and beta-lactoglobin will independently predict decreased development of allergic disease (asthma/wheeze, atopic dermatitis, food allergy, and allergic rhinitis) at age 3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY ENERGY RESTRICTION AND METABOLIC AGING IN HUMANS Principal Investigator & Institution: Roberts, Susan B.; Associate Professor; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 30-APR-2009 Summary: Reducing morbidity and delaying mortality are recognized as major goals of aging research, and are addressed by this proposal to conduct a 2-year human caloric restriction (CR) intervention. A 1-year pilot study will be conducted in 32 overweight men and women to develop an effective CR regimen when fed at 70% of energy requirements determined at baseline. As part of this pilot we will refine all aspects of a CR intervention, including exercise and behavioral counseling, and will obtain necessary information on outcome variability with which to perform power calculations for the main study. Subjects will be randomized to two dietary regimens with different levels of dietary fat and glycemic index (GI) (20% fat and moderate GI vs. 35% fat and low GI) and dietary compliance and key outcome measurements will be determined at 5 periods throughout the year. Dietary factors such as dietary variety, liquid sources of energy, and dietary fiber will then be taken into account in the design of the interventions. Following identification of an effective CR regimen, a randomized 2- year intervention will be conducted in 117 overweight men and women fed 70%, 80% or 100% of energy requirements determined at baseline. The hypothesis will be tested that, compared to control subjects fed 100% of baseline energy requirements. The parameters to be evaluated will include immune function, oxidative stress, fasting insulin, hemoglobin Alc, and cardiopulmonary function. W further hypothesize that, compared control subjects, individuals randomized to 70% or 80% of baseline energy requirements will not experience adverse change sin thyroid and reproductive hormones, bone mineral density, disease incidence, mood or cognitive function. Dose-response relationships between the extent of CR and changes in outcome variables are anticipated. As part of the study, changes in total energy expenditure and resting metabolic rate, body composition and body temperature will be quantified to document the effects of CR on energy metabolism. We anticipate that the results of this study will have a major impact on our understanding of the relevance of CR to human health. In addition, this study will contribute to the development of new avenues for long- term treatment of overweight and obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIETARY FAT IN PREVENTION OF PROSTATE CANCER Principal Investigator & Institution: Aronson, William J.; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): International incidence patterns and migration studies, epidemiological data, and animal and in vitro studies suggest that high-fat diets rich in omega-6 fatty acids increase the risk of developing prostate cancer. The mechanisms by which dietary fat promotes prostate carcinogenesis are not completely known, thus complicating the identification of intermediate markers of activity or efficacy for dietary intervention. Recently, our laboratories have completed a series of studies demonstrating the ability of a low fat diet to inhibit the growth of human prostate cancer in a SCID mouse model, and the ability of omega-3 fatty acids to inhibit the growth of prostate cancer in vitro. In parallel, we have conducted two dietary intervention trials in humans in order to identify potential serum bioassays and serum and tissue biomarkers of the effects of low fat and high omega-3 fatty acid diets. Based on our prior studies, we hypothesize that serum and tissue biomarkers can be developed that correlate with anti-tumor activity and may serve as intermediate endpoints for large-scale prostate cancer prevention trials. To test this hypothesis we propose two Specific Aims: Aim 1. To evaluate the ability of a low fat diet high in omega-3 fatty acids to prevent prostate cancer and to correlate intermediate serum and tissue biomarkers/bioassays with dietary efficacy in pre-clinical models of prostate cancer. Aim 2. To validate the intermediate biomarkers from Aim I in a dietary intervention trial of men undergoing radical prostatectomy. The ultimate goals of our project are (1) to identify the most promising diet (vis a vis fat content) for future prevention trials and (2) to identify markers (particularly in serum) that correlate with dietary activity and may be useful as intermediate endpoints for these trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIETARY FLUORANTHENE

FAT

MODULATED

METABOLIC

FATE

OF

Principal Investigator & Institution: Ramesh, Aramandla; Pharmacology; Meharry Medical College 1005-D B Todd Blvd Nashville, Tn 37208 Timing: Fiscal Year 2003; Project Start 06-MAY-2003; Project End 30-APR-2006 Summary: (provided by applicant): Many hydrophobic and lipophilic environmental toxicants when consumed through diet are absorbed by passive diffusion across the gastrointestinal tract. The extent of absorption of these chemicals during gut passage and the factors governing their absorption are critical in determining the absorption efficiency of chemicals ingested through diet. In this research we will test the hypothesis that lipid load in the diet modulates fluoranthene (FLA; a toxic, and mutagenic polycyclic aromatic hydrocarbon compound) absorption resulting in conversion of FLA to its reactive metabolites in the body and in the extent of DNA-adduct formation. We propose the following three specific aims to test the hypothesis i) to study the bioavailability, metabolism and toxicokinetics of orally administered FLA and the fate of reactive metabolites in different concentrations of dietary fat and at different doses, ii) to estimate the disposition of FLA using a physiologically based pharmacokinetic model, and iii) to investigate the influence of dietary fat on formation and persistence of FLADNA adducts in target tissues. Our expectation is that findings from this research will provide us with a comprehensive picture of the fate and consequences of carcinogenic chemicals ingested through lipid rich diet. Results from these studies are significant in

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Dietary Fat

that they contribute to a greater understanding of the role played by dietary modulation on disposition of FLA in the body and the mechanisms by which bioavailable dose contributes to carcinogenicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION Principal Investigator & Institution: Jump, Donald B.; Professor; Physiology; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2001; Project Start 01-AUG-1991; Project End 31-JUL-2004 Summary: The quantity and type of dietary fat ingested contributes to health as well as the onset and progression of several chronic diseases. The liver plays a central role in whole body lipid synthesis and metabolism. Past studies conducted by the PI have focused on defining the molecular basis of fatty acid regulation of transcription of genes encoding proteins involved in fatty acid synthesis and oxidation. These studies have revealed 3 distinct mechanisms for fatty acid control of hepatic lipid metablosim: a) highly unsaturated n-3 fatty acids activate the peroxisome proliferator activated receptor (PPAR alpha) and induce the expression of genes involved in peroxisomal and microsomal fatty acid oxidation; b) n-3 and n-6 polyunsaturated fatty acids (PUFA) suppress the nuclear content of the sterol response element binding protein, SREBP1c. SREBP1c plays an important role in the control of lipid synthesis and storage; c) conversion of n-6 PUFA to prostanoids activated G-protein linked receptors in parenchymal cells and cultured adipocytes to suppress mRNAs encoding specific lipogenic genes. Of these 3 pathways, PUFA control of nuclear SREBP1c (nSREBP1c) level appears central to the regulation of hepatic lipid synthesis. However, the molecular basis for this control is not well understood. Moreover, studies show dysregulation of SREBP1c and microsomal fatty acid oxidation in livers of obese mice. Dietary fat control of nSREBP1c levels requires microsomal fatty acid oxidation is the hypothesis that will be tested. Changes in hormonal and/or nutrient intake accompanying obesity alter microsomal PUFA metabolism which impacts SREBP1c levels and contributes to the dysregulation of hepatic lipid metabolism. In this proposal,four aims are designed to answer the following questions: 1) How does SREBP1c functionally interact with nuclear receptors? 2) How does PUFA regulated hepatic SREBP1c levels? 3) Is microsomal fatty acid metabolism involved in regulating nSREBP1c abundance? 4) Is aberrant fatty acid metabolism associated with the dysregulation of nSREBP1c and lipogenic gene expression in livers of obese mice? Obesity is a growing human health issue worldwide and risk factor for chronic diseases, like hypertension, insulin resistance heart disease and cancer. PPAR alpha and SREBP1c are key hepatic transcription factors involved in partitioning lipid between synthesis/storage and oxidation. Understanding how these factors participate in this process in normal and obese animals will have important implications for human health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIETARY FAT, PLASMA LIPIDS AND OTHER CHD RISK FACTORS. Principal Investigator & Institution: Lichtenstein, Alice H.; Professor; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-AUG-2004 Summary: (Adapted from Investigator's Abstract) The objective of this application is to assess the impact of newer approaches to dietary modification with the intent of

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reducing the risk of developing cardiovascular disease. The specific aims of the application are as follow: 1) to assess the impact of substituting two classes of fats specifically formulated to substitute for hydrogenated fats (i.e., trans-free margarines and genetically modified/selectively bred oils) on serum lipid levels (total, VLDL, LDL, HDL, HDL2 and HDL3 cholesterol; triglyceride; apo A-l and B; Lp[a]), immune function, and prostaglandin levels, and 2) to address unresolved issues related to plant sterols, including the relative efficacy of currently available preparations, impact of the fat and cholesterol content of the diet, and effect of dosing frequency on serum lipids, endogenous cholesterol synthesis, cholesterol absorption, and fat soluble vitamin levels. Study subjects will be older (50-75 y) hypercholesterolemic female and male subjects (LDL cholesterol 130-160 mg/dl). Each 5-week diet phase will be scheduled in randomized order; all food and drink will be provided. In Part 1, Study 1, subjects will consume each of 3 diets (30 percent fat [2/3 experimental fat], 80 mg cholesterol/1000 kcal) with the following experimental fats: conventional soft margarine; trans-free margarine (interesterified palm kernel + liquid oil); trans-free margarine (fully hydrogenated soybean oil + liquid oil). In Part 1, Study 2, subjects will consume each of 6 diets (as above) with the following experimental fats: hydrogenated soybean (shortening), high oleic sunflower, high oleic soybean, high oleic canola, low saturated soybean and low linolenic soybean oils. In Part 2, Study 1, subjects will consume each of 4 diets (38 percent fat [15 percent SFA, 14 percent MUFA, 6 percent PUFA], 200 mg cholesterol/1000 kcal), baseline and the following: sitostanol ester; sitostenol ester, and genetically modified high sterol oil. In Part 2, Study 2, subjects will consume each of 4 plant sterol enriched diets, high fat (as above) with high (200 mg) or low (80 mg) cholesterol/1000 kcal, and low fat (20 percent fat [5 percent SFA, 7.5 percent MUFA, 7.5 percent PUFA]) with high or low cholesterol. In Part 2, Study 3, the effect of dosing regime will be assessed using the most efficacious plant sterol as identified in Study 1 and diet as in Study 2 (single bolus or in 3 divided doses). There is a rapid introduction of foods designed to optimize blood lipid levels into the marketplace. Limited data are available on efficacy, especially within current U.S. dietary patterns. Virtually no information is available on the effect of altering the fatty acid profile of the diet on biological parameters other than serum lipids. The investigators state that data derived from the proposed studies could contribute to the database on which to formulate more specific public health recommendations regarding the variables described. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY INTERVENTION--WOMEN HIGH RISK FOR BREAST CANCER Principal Investigator & Institution: Djuric, Zora; Associate Professor; Internal Medicine; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 27-FEB-1997; Project End 31-DEC-2002 Summary: (Applicant s Description) Dietary fat intake and consumption of fruits and vegetables have been suggested to influence breast cancer risk in women. Testing this hypothesis, however, requires quantitative markers of breast cancer risk that will allow assessment of the effect in a timely manner. To evaluate the beneficial effect of reducing and/or increasing the intake of fruits and vegetables on cancer risk in the proposed clinical trial, the applicant plans to measure the levels of oxidative DNA damage and cholesterol oxides. These intermediate biomarkers are indicative of oxidative stress levels, and oxidative stress has been associated with breast cancer risk. Eligible women who have first degree relatives with breast cancer will be recruited from a high-risk clinic. The women who enter the trial will be randomized onto one of four diets: 1)

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Dietary Fat

control, 2) low-fat (15 percent of caloric intake without altering intake of fruits and vegetables), 3) high fruit/vegetable (8 servings/day without altering fat intake), and 4) a low-fat diet that is also high in fruits and vegetables. We plan to retain 30 women/diet arm. The 12-month intervention will involve individualized dietary counseling that meets the needs and abilities of each woman. Blood samples, breast fluids (obtained by expression from the nipple) and complete dietary analyses of four-day food records will be obtained at study entry and at regular intervals during the 12 month program. The levels of 5-hydroxymethyl-2'-deoxyuridine, an oxidized thymidine residue, will be assessed in DNA from blood by gas chromatography-mass spectrometry (GC-MS). The levels of cholesterol oxide in serum and breast fluids will be assessed by GC. The morphology of cells in the breast fluids will be assessed by image analysis since morphological changes are expected to be related to levels of oxidative stress. The levels of micronutrients (carotenoids and tocopherols) in serum and breast fluids also will be determined and used as a monitor of fruit and vegetable intake. In addition, micronutrient levels may well influence the other biomarkers. This research on the biological effects of diet in women at high risk for breast cancer is responsive to the "Healthy People 2000" objective of cancer prevention. The use of biomarkers will allow to evaluate the cancer-protective effects of dietary modulation over a relatively short period of time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY OBESITY Principal Investigator & Institution: Bray, George A.; Director; None; Lsu Pennington Biomedical Research Ctr 6400 Perkins Rd Baton Rouge, La 70808 Timing: Fiscal Year 2001; Project Start 01-AUG-1982; Project End 31-JUL-2003 Summary: The objective of this research grant is to characterize the mechanisms for the differences between two strains of rats which differ in their susceptibility to obesity when eating a high fat diet. The Osborne- Mendel rat (OM) rapidly becomes obese when maintained on a high fat diet while the S5B/PI (S5B) rat remains lean when eating the same diet. We have recently demonstrated that the OM rat increases its intake of a high fat diet after administration of the 5-HT1A agonist, 8-hydroxy-2- (di-nproplyamino)tetralin, which inhibits serotonin synthesis and release. S5B rats do not increase food intake after this treatment. In addition, fenfluramine treatment prevents high fat diet-induced obesity in the OM rat. This proposal focuses on the mechanisms underlying two aspects of this dietary-induced obesity. Our first aim will be to elucidate the central nervous system neurotransmitter signals that mediate fat preference by examining the serotonin system in these two rat strains. We will test the hypothesis that the serotonergic system is more active in the S5B rat than the OM rat. The first three experiments in this aim will investigate the effects on food intake in OM and S5B rats by altering serotonin levels in the paraventricular nucleus. The next five experiments will determine the contribution of the dorsal raphe nucleus to the serotonin systems in OM and S5B rats. The last two experiments will examine the hypothesis that opioids in the hindbrain may modulate the serotonergic signals from the paraventricular nucleus. We will utilize the novel technique of central antisense oligonucleotide application in two critical experiments to test these systems. The second aim will examine the difference in peripheral signaling systems that responds to nutrient infusion in these two rat strains. We will test the hypothesis that fatty acids in the GI tract activate vagal mechanisms more effectively int the S5B rat. We have already demonstrated that S5B rats are much more sensitive to the satiating effects of intraintestinal fat infusions. There are seven experiments proposed which will examine the involvement of the vagus nerve,

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cholecystokinin, glutamate, c-fos activated neurons and serotonin in the differential responsiveness to nutrient infusion in OM and S5B rats. Our laboratory has made significant advances toward understanding dietary-induced obesity. We now propose these well founded, important and exciting studies which will provide critical new insights into anatomical, physiological and molecular mechanisms by which high levels of dietary fat induce obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY VARIETY VS DIETARY FAT EFFECTS ON ENERGY INTAKE Principal Investigator & Institution: Mccrory, Megan A.; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The relative importance of dietary patterns vs. macronutrient composition in affecting energy intake and body weight remains uncertain. In this study we propose to investigate the relative effects of dietary variety versus dietary fat on voluntary energy intake in adults. Specifically, we will quantify and compare the effects of typical ranges of variety and fat intakes in the American diet (based on U.S. national survey data) on voluntary energy intake. The primary hypotheses to be tested are (1) an increasing availability of entree/side/snack/dessert variety offered will significantly increase voluntary energy intake in a dose-response fashion when other dietary factors known to influence energy intake are held constant (including macronutrient composition, palatability and variety of other food items); and (2) the separate effects of dietary variety and dietary fat on energy intake will be similar. Healthy, weight stable men and women (n=96, aged 18-45 y, BMI 20-35 kg/m2) will be recruited for a 39-d study in which food is provided. Three levels of entree/side/snack/dessert variety will be offered at each of three levels of dietary fat intake, and the relative effects of these dietary manipulations on voluntary energy intake, independent of potentially confounding dietary factors, will be quantified. Subjects will be assigned to one of three BMI-matched groups that will be offered either 4, 8 or 12 entree/side/snack/dessert items/d at one of three fat intake levels (20, 35, or 50 % of energy) in each of three 13-d phases. All diets will be matched for palatability, fiber, protein content, and the variety of other food items, and also for energy density at each fat intake level. Daily voluntary energy intake will be measured and dietary compliance monitored by using measurements of 24-h urinary PABA and osmolar excretion rates. Other measurements include food and meal palatability, hunger, desire to eat, dietary disinhibition, energy expenditure, and body weight and composition. We anticipate that the results of this investigation will lead to a greater understanding of the relative importance of eating patterns vs macronutrient composition in the etiology of obesity, and more specifically, dietary variety versus dietary fat in determining energy intake. Most importantly, it will help lay a foundation for improved dietary recommendations concerning weight loss and prevention of excess weight gain in adulthood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIFFERENTIAL METABOLISM OF DIETARY FATTY ACIDS Principal Investigator & Institution: Kien, C L.; Professor; Pediatrics; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004

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Dietary Fat

Summary: Preliminary data indicate that the rate of oleic acid oxidation is 21 percent increased compared to palmitic acid. If the ratio of OA to PA in the diet were to increase, the rate of total fatty acid oxidation in the fed state also may increase; thus, daily fat balance might be decreased in humans fed diets enriched in OA. This would have significance to the treatment and prevention of obesity. Indirect calorimetry will be performed in the fed and fasting state in 34 young, healthy adults who will be studied under two conditions: after a 30-day, solid food diet ("run-in phase") and again, after a 30-day formula diet. The subjects will be randomized to receive either a Control Formula similar to the solid food diet (OA=PA=16.4 percent total kcal) or a High Oleic Acid Formula (OA=31.4 percent kcal; PA=1.7 percent kcal). Using dual-energy x-ray absorptiometry, body composition will be monitored before and after the formula diet. The principal investigator (PI) will address four specific aims. In specific aim 1, the PI will determine if a higher intake of oleic acid (and a reciprocally lower intake of palmitic acid) is associated with a higher rate of fat oxidation. The PI hypothesizes that the rate of fat oxidation (g/hr) in the fed state, adjusted for the covariate effect of the rate of fat oxidation on the solid food diet, will be higher (30 percent) in those subjects randomized to the OA-enriched diet compared to controls. In the specific aim 2, the PI will measure energy intake required to maintain constant body weight during each diet and to measure fat-free mass and fat mass, before and after each dietary change. The PI hypothesizes that a higher rate of fat oxidation on the high OA diet will be associated with a higher energy intake required to maintain constant body weight. In specific aim 3, the PI will compare fat oxidation on the liquid formula diet with that observed on the solid food diet. The PI hypothesizes that fat oxidation will increase in those fed the OAenriched diet. In specific aim 4, the PI will measure the thermic effect of feeding during both the solid food and formula diet periods. The PI hypothesizes that the high OA feeding will be associated with a higher thermic effect of feeding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF CHRONIC AMYLOSE FEEDING IN ADIPOSITY Principal Investigator & Institution: Bessessen, Daniel H.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Currently, there is strong evidence linking dietary fat intake to the development of obesity but very little is known about the effects of carbohydrate subtype on this disease. However, recent evidence from both rat and human studies suggest that carbohydrate subtype may have direct effects on lipid metabolism. Dietary carbohydrates consist of simple carbohydrates, or sugars, and complex carbohydrates, or starches. All starch is comprised of two polymers of glucose amylose or amylopectin, in different proportions. Rat data indicates that long-term amylopectin feeding causes insulin resistance relative to amylose feeding. In addition, it has recently been shown that amylose feeding effects adipocyte morphology in rats reducing cell size and increase cell number compared with amylopectin- feeding. Also, low glycemic index diets (amylose) seem to increase HDL- cholesterol compared with high glycemic index diets (amylopectin). The studies proposed in this application aims to determine the effects of long- term amylose/amylopectin feeding on adiposity and metabolic profile. The specific aims are: 1) to define the dose-response relationship between the amylose content of the diet and postprandial glycemic/insulinemic response; 2) to measure adipocyte cell size and number in response to a high amylose diet; 3) to correlate any changes in adipocyte morphology with body composition; 4) to measure insulin sensitivity in response to the amylose content of the diet; 5) to determine the effects of

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the amylose content of the diet on macronutrient storage and utilization. The optimal amylose content in the diet, as determined by meal tests which define the dose-response relationship between the amylose content of the diet and postprandial glycemic/insulinemic response, will be used in a chronic amylose /amylopectin feeding study. Subjects will be randomly assigned to an amylose- or amylopectin-based diet for 12 weeks in a double cross-over blinded design. One group of subjects will consume an amylose-based diet for 12 weeks followed by a 4 week wash out period and conclude the study with 12 weeks on an amylopectin-based diet. The second group shall receive the two diet phases in reverse order (i.e. amylopectin followed by amylose). At he beginning and end of each diet phase adipocyte cell size and number, body composition, macronutrient oxidation rate, insulin sensitivity, and fasting and postprandial blood lipids, glucose, insulin and leptin concentrations will measured. By using this study to define the role of carbohydrate subtype on adiposity and the metabolic changes associated with obesity, we are moving a step closer to the overall aim of this research which is to develop an "anti-obesity" diet. Such a diet would optimally combine the fat and carbohydrate subtypes which most effectively prevent adiposity and the metabolic changes associated with obesity, we are moving a step closer to the overall aim of this research which is to develop an "anti- obesity" diet. Such a diet would optimally combine the fat and carbohydrate subtype which most effectively prevent adiposity and weight gain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF DIET ON INSULIN SENSITIVITY AND ENERGY BALANCE Principal Investigator & Institution: Hays, Nicholas P.; Geriatrics; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): The broad, long-term objective of this research proposal is to improve the health and well being of the elderly via decreased risk for type 2 diabetes. The specific aim of the project is to examine the influence of an ad libitum 12- week low-fat/simple-carbohydrate diet, with and without aerobic exercise training, on body mass, energy balance, and insulin sensitivity in older subjects with impaired glucose tolerance. Preliminary data indicate that consumption of a lowfat/complex-carbohydrate diet, with no attempt at energy restriction, results in loss of body weight and improvement in insulin sensitivity. We hypothesize that replacement of dietary fat with simple rather than complex-carbohydrates will result in similar improvements in health. Thirty-six overweight men and women aged 55-80 years with impaired glucose tolerance will be randomized into one of three groups. Group 1 will receive a control diet (similar to baseline intake), group 2 will receive a low-fat/simplecarbohydrate diet (17% fat, 16% protein, 67% carbohydrate, 9g fiber/1000kcal), and group 3 will receive an identical low-fat diet and be placed in an aerobic exercise training program (4d/week, 80% VO2ma,). Body composition will be measured using air displacement plethysmography, energy and macronutrient metabolism will be measured using whole room calorimetry and de novo lipogenesis, and insulin sensitivity will be measured using a euglycemic-hyperinsulinemic clamp. Given the increasing prevalence of type 2 diabetes in the elderly U.S. population, completion of this project will more clearly define the specific dietary and exercise interventions that have the greatest potential positive impact on health in older individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT CHYLOMICRONS

OF

DIETARY

LIPIDS

ON

THE

FUNCTION

OF

Principal Investigator & Institution: Chung, Byung-Hong H.; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 15-SEP-1999; Project End 31-AUG-2003 Summary: Although numerous diet studies have demonstrated that dietary fat composition of chronic diets alters fasting plasma lipoprotein cholesterol (CH) levels and the risk of developing atherosclerosis, the specific mechanisms responsible for these alterations are not well established. Dietary fat and CH are the exclusive precursors of postprandial (PP) chylomicrons, but they do not enter into the formation of endogenous lipoproteins in fasting blood. The working hypothesis of this proposal is that dietary fat composition alters endogenous lipoprotein CH levels in fasting plasma and the risks of developing atherosclerosis by influencing the ability of PP chylomicrons to accept CH molecules from endogenous lipoproteins and cell membranes through the reactions catalyzed by lecithin cholesterol acyltransferase (LCAT) and/or cholesterylester transfer proteins (CETP) and by influencing the rate of the clearance of CH-enriched chylomicron remnants from circulating blood. To test this hypothesis, this study will examine the acute and chronic effect of altering dietary fat composition on 1) level, composition and density spectrums of plasma lipoprotein CH and TG, 2) the extent of LCAT and CETP-mediated transfer of CH from endogenous lipoproteins and/or cell membranes into PP TG-rich lipoproteins in vivo and in vitro, 3) intraplasma metabolic activities that promote the reverse cholesterol transport (RCT) in vivo and 4) the extent of accumulation of chylomicrons and their remnants in the blood at a late clearance stage of PP lipemia. Study subjects (n=32) will be recruited from a pool of normolipidemic adult males and will be rotated through three experimental diets (saturated fat, polyunsaturated fat, and monounsaturated fat), each diet lasting for 20 days. Three oral fat loading studies will be conducted during each dietary intervention period. Each subject will serve as his own control. The studies determining the chronic and acute effect of dietary fat composition on the potencies of PP chylomicrons to accept CH from endogenous lipoproteins and cell membranes and to deliver their CH to the liver for excretion should provide additional information about the mechanisms by which the dietary fat composition alters the development of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF A HIGH GLYCEMIC LOAD DIET ON VASCULAR SYSTEM Principal Investigator & Institution: Rutledge, John C.; Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Recent dietary guidelines recommend a low fat, high carbohydrate diet. However, data from a variety of sources indicate that diets containing carbohydrate primarily as simple sugars increase cardiovascular risk. The mechanisms of this increased risk are yet to be fully understood. The parent study of this proposal seeks to understand the metabolic consequences of consuming a diet with a low glycemic load versus a diet with a high glycemic load in overweight women. Our ancillary study will extend the parent project by examining some of the cardiovascular consequences of these diets and the mechanisms of the cardiovascular consequences in subjects who consume these diets. Our goals are first to determine if consuming a high glycemic load diet activates endothelium, platelets and monocytes. Second, we will

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examine mechanisms by which postprandial triglyceride-rich lipoproteins (TGRL) generated by these diets induce arterial injury. We expect that a high glycemic load diet with the accompanying increase in postprandial TGRL will increase platelet and monocyte activation and increase adherence of these cells to endothelium. Further, we expect that high levels of ongoing TGRL lipolysis will increase endothelial layer permeability. The increase in endothelial layer permeability will enable more and larger postprandial lipoproteins to enter the artery wall and localize on the endothelial cell luminal surface and in the subendothelial space. Contrasting sources of dietary carbohydrate may have distinctive influences on the fate of dietary fat. Eating a high carbohydrate, low glycemic load diet may improve fat metabolism, reduce cardiovascular risk factors, and suppress hunger in overweight women. Ultimately this type of diet may be a good alternative to restricting calories for weight management. We urgently need more information about the cardiovascular consequences of some of the commonly used diets in order to properly advise individuals and the public at-large about the long-term consequences of dieting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF DIET ON GROWTH HORMONE-IGF-1 AXIS Principal Investigator & Institution: Boyd, Norman F.; Ontario Cancer Institute 610 University Ave Toronto, Timing: Fiscal Year 2001; Project Start 19-SEP-2001; Project End 31-AUG-2003 Summary: The specific aim of this proposal is to determine whether In premenopausal and postmenopausal women blood levels of Insulin like Growth Factor-I, Insulin like Growth Factor Binding Protein -3 and Growth hormone are influenced by a low-fat high- carbohydrate diet. The general method to be employed will be to perform assays for growth factors and hormone on blood samples, and nutrient analysis of food records, collected from subjects taking part in our ongoing multicentre randomized dietary intervention trial. This trial is designed to test the hypothesis that intervention with a low-fat high-carbohydrate diet will, in women with extensive mammographic densities, over a 10 year period reduce the incidence of breast cancer by 29 percent. The trial is explanatory in that it seeks to determine if there is a biological effect of dietary fat reduction in terms of a reduction in breast cancer incidence. To meet this goal we have selected as participants highly motivated subjects who are at increased risk of breast cancer, we have provided them with a high level of assistance in making a dietary alteration, we follow them carefully to ensure the maintenance of dietary change and the correct identification of subjects who develop breast cancer, and we plan to analyse the results according to study group and dietary compliance. Recruitment of the 4615 subjects required for the trial was completed in November 1998. (A total of 4693 were randomized). Blood samples and food records from subjects enroled in the trial will be used to test the hypotheses given below about the effects of dietary intervention on growth factors and hormones associated with breast cancer risk. Modulation of these factors by dietary intervention would indicate potential mechanisms by which diet may influence risk of breast cancer. Although not the purpose of the research proposed here, the long term nature of the trial, the complete follow-up of all subjects, and the complete ascertainment of breast cancer, will ultimately allow any changes in blood markers found in the present research to be examined in relation to changes in breast cancer incidence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS METABOLISM

OF

LIPID

OXIDATION

PRODUCTS

ON

BONE

Principal Investigator & Institution: Parhami, Farhad; Associate Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (provided by the applicant) Age-related osteoporosis is characterized by decreased osteoblast number and bone forming activity, and increased bone marrow adipocyte content. This suggests a shift in bone marrow mesenchymal stem cell (MSC) differentiation pathways, with increased adipocyte and decreased osteoblast production. The mechanisms underlying these changes have not been defined. Recently, our laboratory has demonstrated that lipid oxidation products (LOPs) inhibit the differentiation of preosteoblastic cells into osteoblasts and promote their adipogenic differentiation in vitro, in parallel with altered responsiveness to bone morphogenic protein-2 (BMP2) and other bone-growth factors. Moreover, mice fed an atherogenic high-fat diet exhibited decreased bone mineral density (BMD) and a reduced capacity of their MSCs to differentiate into osteoblastic cells in vitro. Therefore, it is hypothesized that LOPs contribute to age-related osteoporotic bone loss by decreasing bone cell growth factor production and/or responsiveness, and enhancing adipogenic differentiation of bone marrow stem cells at the expense of osteoblast production. To examine this hypothesis, we will pursue the following specific aims: 1) further characterize the in-vivo effects of high-fat diet on bone resorption and formation as assessed by quantitative bone histomorphometry, bone turnover markers, and changes in bone mass, in parallel with measurements of serum and bone LOP levels and indices of calcium and vitamin D metabolism; 2) examine the in-vivo effects of high-fat diet on bone marrow stem cell adipogenic (PPARg, aP2, and lipoprotein lipase)and osteoblastic (bone-associated alkaline phosphatase and osteocalcin) gene expression and phenotype; 3 ) determine whether treatment with the dietary antioxidant lutein can inhibit the adverse effects of high-fat diet on bone marrow stem cell differentiation, as assessed by effects on bone histomorphometry and adipocyte vs osteoblast specific gene expression; and 4) further define the in-vivo and direct in-vitro effects of LOPs on osteoblast and osteoblast precursor expression of, and responsiveness to, key bone growth factors including TGF-a, IGF-I/1I and BMP-2/4. In particular, we will pursue our recent observation that LOPs both inhibit BMP2 stimulation of marrow stem cell osteoblastic differentiation and promote adipogenesis in vitro, by examining the mechanisms of this effect in terms of changes in BMP2 type IA and lB receptor expression and second messenger generation. It is anticipated that these studies will identify new targets for interventions to prevent and treat age-related osteoporosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF OVERFEEDING ON OP AND OR WOMEN Principal Investigator & Institution: Bessesen, Daniel H.; Associate Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-APR-2008 Summary: (provided by applicant): Obesity is a serious and growing public health problem in the United States and around the world. While brief periods of positive energy balance likely occur in all people at one time or another, some individuals are able to resist environmental pressure towards weight gain, maintaining a chronic state of thinness. The central thesis of this proposal is that understanding the responses

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(metabolic, energetic, and behavioral) of individuals to short periods of positive energy balance produced by overfeeding, may provide clues as to the biologic mechanisms that either promote or protect against weight gain in the current environment. While long term controlled overfeeding experiments have been done for many years, no previous studies have systematically examined the effects of short-term overfeeding on direct measures of dietary fat oxidation, post overfeeding spontaneous food intake, or physical activity. Further, no previous study has examined the relationship between these variables and subsequent weight gain. It is hypothesized that those individuals who preferentially oxidize dietary fat, reduce food intake and increase physical activity following overfeeding will maintain a thin phenotype over time. Conversely, those who fail to make these adaptations will tend to gain weight over time. The proposed studies will examine the effects of a controlled eucaloric diet or 3 days of feeding 140% of basal energy on 1. The oxidation of 2 dietary fat tracers 2. Hunger, satiety, desire to eat and spontaneous food intake 3. Directly measured levels of physical activity, in a cohort of men and women enriched in individuals likely to maintain a thin phenotype and others selected for a propensity to gain weight. The cohort will then be followed for 3 years to determine the rate of weight gain in each subject. Baseline measures will be correlated with subsequent weight gain in an effort to define which adaptive responses to overfeeding best correlate with longitudinally determined weight gain. By taking a comprehensive approach to examining the responses to overfeeding and future weight changes, the proposed studies should help clarify how homeostatic regulatory mechanisms coordinately respond to a state of short-term positive energy balance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENERGY EXPENDITURE, DIET AND BODY FAT IN CHILDREN Principal Investigator & Institution: Weber, Judith L.; Arkansas Children's Hospital Res Inst Research Institute Little Rock, Ar 72202 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Obesity is highly prevalent in American Indian children, increasing their risk for the development of cardiovascular disease, hypertension and diabetes. Although increasing energy expenditure, through increasing physical activity, and decreasing dietary fat intake should slow the rate of body fat gain, it appears that children actually decrease their physical activity as they mature from pre-to post-pubescence. Several studies have shown that the decline in activity is greater in females than in males, and greater in non-whites than in whites; however, other studies have not supported these findings. Further, there are no data available in American Indian children, which is a population at greatest risk. Additionally, inconsistencies have been reported with respect to the relationship between body weight or body fat and energy intake or dietary fat intake. At the heart of the problem is the difficulty in measuring self-reported physical activity and dietary intake accurately. Accurate self- report measures are necessary for use in the large scale studies that are required to investigate relationships between physical activity and dietary intake and disease. The Healthy People 2000: National Health Promotion and Disease Prevention Objectives include seven objectives emphasizing increasing physical activity in children and adolescents. In support of Healthy People 2000, the National Institutes of Health: National Heart, Lung and Blood Institute has published a Program Announcement (PA-95- 004)entitled, Physical Activity and Cardiopulmonary Health, to solicit well-defined studies in the area of physical activity related to cardiovascular disease risk factors. This study is a combined longitudinal and cross-sectional design in which we will modify the best existing methods for the self-report of physical activity and dietary intake in children and

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adolescents, and evaluate their validity using total energy expenditure (TEE) measured by doubly labeled water (DLW) as the criterion. We will then use these methods to measure physical activity and dietary intake in two age cohorts of male and female American Indian children (8-10-years and 11-13-years) at baseline and two years later, with two sets of interim measurements. Change in TEE from baseline to the two-year follow-up will also be measured using DLW and the TriTrac accelerometer. Equations for the estimation of percent body fat will be cross-validated for this population. The proposed study will fill an existing gap by improving existing instruments for the measurement of physical activity and dietary intake in children and adolescents, and will provide longitudinal data on change in these variables in the same children over time, plus provide cross-sectional data for each age and gender group to compare to the existing literature. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENTEROSTATIN REGULATION OF FAT INTAKE Principal Investigator & Institution: York, David A.; Associate Executive Director/Boyd Profes; None; Lsu Pennington Biomedical Research Ctr 6400 Perkins Rd Baton Rouge, La 70808 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 30-NOV-2005 Summary: This is an application for continuing support for a program focused on the regulatory mechanisms of enterostatin. The peptide enterostatin is a product of a prepeptide called procolipase, which was originally identified in the gut in connection with fat absorption. The previous support for this project has allowed progress in which the investigator has provided evidence for both peripheral and central sites of action for enterostatin. The presumption currently is that the central enterostatin action sites are separate and may be responding to a separate source of enterostatin. Given the current state of knowledge in this area the investigator identifies the following aims for this proposal. First they seek to identify the enterostatin receptor by an expression cloning technique. Second they will characterize the enterostatin receptor and its regulation by dietary fat and by hormones. Third they will investigate how signaling pathways activated by fatty acids in the mouth or gut interact with enterostatin responsive pathways to regulate fat intake. Fourth they will identify the neuropathways responsive to enterostatin by immunohistochemistry and tract tracing techniques. Finally these pathway responsiveness to dietary fat will be evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: FATTY ACIDS AND PPARS IN BREAST CANCER PREVENTION Principal Investigator & Institution: Yee, Lisa D.; Surgery; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: Breast cancer remains the second leading cause of cancer death of women in the United States. Preventive measures with minimal adverse effects are needed to reduce the incidence and progression of breast cancer. The long-term research goal of the principal investigator, Dr. Yee, is to investigate the molecular mechanisms of breast cancer progression and ultimately develop new interventions for breast cancer prevention and eradication. Dr. Yee is requesting funds to develop her skills in breast cancer prevention and control, an effort that will complement her training as a surgeon specializing in breast cancer and allow her to conduct the future translational research vital to reducing breast cancer risk. Her training in preventive oncology will encompass

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mentorship by select faculty of The Ohio State University, Comprehensive Cancer Center and James Cancer Hospital and Solove Research Institute, combining didactic course work and a cancer prevention research project. The plan integrates molecular genetics, nutritional sciences, and clinical breast cancer research. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that stimulate transcriptional activity in response to ligands such as fatty acids and prostaglandins. The PPARgamma subtype regulates cell differentiation and proliferation in normal and malignant tissues. Cell culture and animal models will be used to evaluate fatty acid effects on PPARgamma activation in breast cancer. Human breast tumors and surrounding fat and epithelial tissue will also be assessed for patterns of expression of PPARs and other factors affecting PPAR activation. This work will serve to generate data to support a prospective clinical study of the effects of dietary fat and PPARgamma on breast cancer progression. Combined with a didactic course of study in a stimulating scientific and clinical environment, this project will give Dr. Yee the training required to become an independent clinician scientist in the field of preventive oncology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FFA PRODUCTION FROM TRIGLYCERIDE-RICH LIPOPROTEINS Principal Investigator & Institution: Miles, John M.; Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): The proposed research will continue our work in the area of the regulation of fuel metabolism. Lipid energy is transported in the blood in several forms, including chylomicrons and free fatty acids (FFA). Chylomicrons are key elements in the absorption and storage of dietary fat, and also play a role in the pathogenesis of atherosclerosis via the production of remnant particles. FFA are the major lipid fuel in the body, and increases in their concentration have been shown to cause insulin resistance, endothelial dysfunction, increases in the production of very low density lipoproteins, and increases in blood pressure. FFA are released into the blood through the action of hormone sensitive lipase on triglyceride stores in fat cells. Very little is known about the role of chylomicrons in FFA metabolism, but available evidence suggests that chylomicrons are also a major source of FFA. Extremely accurate and precise methods have been developed by the investigator for the measurement of the concentration and specific activity of FFA and chylomicron triglyceride fatty acids in plasma. In addition, a tracer method for accurately determining the kinetics of chylomicrons has been developed. Preliminary results indicate that approximately 40% of chylomicron fatty acids are released into the circulation as FFA during their metabolism by lipoprotein lipase, and that this release may be greater in adipose tissue than in skeletal muscle. In the proposed studies, the tracer technique will be used to systematically investigate the contribution of chylomicrons to total FFA availability. The technique will be applied to normal subjects at rest and after exercise, as well as subjects with type 2 diabetes mellitus and hypertriglyceridemia. Specifically, these studies will 1) determine the relative contribution of chylomicrons in adipose tissue versus muscle to FFA production and further validate the isotopic method for quantifying chylomicron triglyceride kinetics; 2) determine the relationship between meal fat content and the production of FFA from chylomicrons; 3) characterize FFA production from chylomicrons in subjects with type 2 diabetes and the effect of acute insulin therapy on that process; and 4) determine whether exercise sufficient to lower the chylomicronemic response to a meal results in increased efficiency of regional and systemic chylomicron

34

Dietary Fat

fatty acid uptake in normal subjects. These studies will provide new insights into the regulation of FFA metabolism in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE DIET EFFECTS ON ATHEROSCLEROSIS Principal Investigator & Institution: Breslow, Jan L.; Professor; Lab/Biomed Genetic/Metabolism; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2001; Project Start 01-JUN-1984; Project End 30-JUN-2002 Summary: Atherosclerotic coronary heart disease (CHD) is the number one public health problem in the United States. CHD has been increasing in prevalence and with the aging of the baby boomers and the increase in major cardiovascular risk factors in the population (smoking, obesity and physical inactivity) over the last 10 years the problem will be even worse in the 21st century. This is not just a U.S. problem, but is occurring world wide. The WHO has recently predicted that by 2020 heart disease will replace infectious disease worldwide as the number one cause of disability expressed as years of healthy life lost to death or disease. CHD is considered a complex genetic disease with many genes involved and important gene-environment interactions. Cross cultural studies and human and animal feeding studies have clearly established a role for diet, particularly a high saturated fat, high cholesterol diet in atherosclerosis susceptibility. However, clinical studies have also established that there is great variation between people in diet responsiveness of their plasma lipoprotein pattern and presumably, although it has not been studied directly in humans, dietary effects on atherosclerosis susceptibility. Thus a better understanding of gene diet interactions as they effect lipoprotein levels and atherosclerosis susceptibility should lead to better ways to identify and treat individuals susceptible to CHD in the population. In the current competing renewal, I propose to use induced mutant mouse models to better understand the regulation of dietary cholesterol absorption and how dietary fats influence atherosclerosis susceptibility. The following specific aims are proposed: Determine the mechanism of regulation of dietary cholesterol absorption through the study of mutant mice; positional cloning of genes that regulate dietary cholesterol absorption by interbreeding mouse strains that differ in dietary cholesterol absorption; determine the effects of diets enriched in carbohydrate, saturated fat, monounsaturated fat, or polyunsaturated fat on atherosclerosis susceptibility and the mechanisms of the dietary effects observed using induced mutant mouse models of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE EXPRESSION IN DIET INDUCED PROSTATE CANCER Principal Investigator & Institution: Geliebter, Jan; Microbiology and Immunology; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2001; Project Start 05-FEB-2001; Project End 31-JAN-2003 Summary: Epidemiological studies suggest that a high fat diet for more than one generation is associated with an increased risk of prostate cancer. A more complete understanding of the molecular basis for prostate cancer initiation, promotion and progression by dietary fat is essential for the design of rational programs for prostate cancer prevention and treatment. We have maintained ACI rats on a high beef fat diet (22.52% by weight) for two generations (mothers and male pups) and observed that 2nd-generation male rats develop prostatic neoplasia at a higher incidence, and earlier in life, than rats on a control, 5% fat diet. It is significant that rats on the high beef fat diet developed neoplasia in the dorsal lobes of the prostate, as the dorsal lobe of the rat

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prostate is homologous to the peripheral zone of the human prostate, where prostate cancer is most prevalent. All animal studies and histological analyses have been completed and we have prepared RNA from dorsal prostates of 6, 12 and 18-month-old 2nd-generation rats. We now propose to analyze the molecular differences in the dorsal prostates of rats maintained on a high fat diet, compared to rats on a control diet to follow gene expression through the progressive molecular stages of diet-induced prostatic neoplasia. We propose to use Affymetrix microarrays (approximately 7000 genes) to identify differences in mRNA expression profiles in the dorsal prostates of rats on high beef fat and control diets. Further we propose to use northern blots and immunohistochemistry to confirm data obtained using microarrays and to identify the cell types differentially expressing the genes in question. The successful completion of these experiments will contribute to our understanding of the molecular basis of dietassociated prostate cancer. Further, it can potentially identify intermediate biomarkers that are modulated by diet and are relevant to human prostate cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC TRIGLYCERIDES

AND

ENVIRONMENTAL

DETERMINANTS

OF

Principal Investigator & Institution: Arnett, Donna K.; Associate Professor; Epidemiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Hypertriglyceridemia is emerging as important predictor of atherosclerosis, and recent evidence suggests related phenotypes of triglycerides (TGs), such as TG remnant particles and small LDL particles, are particularly atherogenic. There is considerable variation in the response of TGs and related phenotypes to the environment. The aim of the proposed study is to characterize the genetic basis of the variable response of TGs to two environmental contexts, one that raises TGs (dietary fat), and one that lowers TGs (fenofibrate treatment). We will recruit 2,400 family members from 3-generational pedigrees of the ongoing NHLBI Family Heart Study (FHS) in two genetically homogeneous centers (Minneapolis and Salt Lake City). We will collect measurements before and after a dietary fat challenge to assess postprandial TGs and related atherogenic phenotypes (VLDL TGs, chylomicron TGs, TG remnant particles, HDL and LDL particle sizes, total cholesterol, LDL-C, and HDL-C). In families with 2 or more members in a sibship with TGs >= 130 mg/dl, we will conduct a short-term, placebo-controlled, randomized trial of fenofibrate in all willing and eligible family members (anticipated sample size = 1,200). A two-period crossover design will be executed with a 2-week washout between two 3-week treatment periods (placebo or micronized fenofibrate, 160 mg). About 1,000 family members have a Marshfield genome marker set available as part of NHLBI FHS; the remaining 1,400 will be typed using the same marker set. We will conduct genome-wide linkage analyses using stateof-the-art methods to localize novel genetic loci contributing to TG response in the context of fat loading and fenofibrate treatment. We will type 15 single nucleotide polymorphisms (SNPs) in ten candidate genes known to contribute to the response of TGs to dietary fat and fenofibrate, and create haplotypes for association studies. We will use combinatorial partitioning methods and neural networks to test association of the individual SNPs and haplotypes with response to the two environmental interventions. The identification of genetic loci that predict TG response in the presence of two disparate contexts, fat loading and fibrate therapy, may provide insights into genetic pathways (a) predisposing to hypertriglyceridemia, ultimately leading to avenues for

36

Dietary Fat

primary prevention, and (b) predicting response to TG lowering, leading to new drug targets for hypertriglyceridemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC BASIS OF DIETARY OBESITY IN MICE Principal Investigator & Institution: Cheverud, James M.; Professor; Anatomy and Neurobiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2003 Summary: In humans, individuals vary in their response to dietary fat. Some individuals gain substantial amounts of weight and fat while other individuals gain little on a high fat diet. There is some evidence that variability in response to a high fat diet may have a genetic basis in humans. The main goal of the proposed project is to map and measure the effect of genes on the response to a high fat diet in a new multigenic obesity model, strains derived from the intercross between SM/J and LG/J inbred mouse strains. The SM/J and LG/J strains show substantial differences in body size and fatness. They also differ dramatically in their response to a high fat diet. Dietary responses vary with age. A series of 40 recombinant (RI) strains derived from the SM/J by LG/J cross will be brought to effectively inbred status (F greater than 0.98). These strains will then be used to map genes for dietary obesity by measuring variability in the response of each RI strain to a high fat diet. Sixteen animals from each strain will be fed the high and low fat diets. Interval mapping will be used to localize quantitative trait locus effects on dietary obesity to a 10-20 cM interval. A single Advanced Intercross (AI) line will be maintained and used to fine-map QTLs discovered in the RI strain analysis to a 1-2 cM interval. This project will be the first to detect and map genes specifically affecting response to a high fat diet. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLYCEMIC INDEX AND METABOLIC SYNDROMEN Principal Investigator & Institution: Pittas, Anastassios G.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2006 Summary: (provided by applicant) The increase in the prevalence of obesity and related conditions such as type 2 diabetes mellitus (DM-2) and cardiovascular disease has taken place despite a decrease in the percentage of energy intake derived from daily dietary fat over the last 20 years. This observation suggests that factors other than dietary fat intake may be responsible for the observed increase in obesity and associated conditions. One such factor regulating weight and also directly influencing the morbidity and mortality associated with obesity is the dietary glycemic index (GI). In this study, we propose to investigate the association of dietary GI with intermediary predictors of long-term health outcomes related to DM-2 and its associated increased cardiovascular disease. In a 1-year weight loss study, we will compare two caloric restricted interventions providing 70 percent of baseline energy requirements of variable GI (20 percent fat and moderate GI vs. 35 percent fat and low GI) in 32 healthy men and women aged 30-40 years with initial values for body mass index (BMI) of 25-34.9 kg/m2. The following single-blinded outcome measurements will be made at baseline and at 1, 4, 8 and 12 months: (A) Body composition (fat, fat free mass and truncal/total fat) will be determined by dual x-ray absorptiometry (DXA). (B) Markers related to DM2: central adiposity (truncal/total fat) by DXA and by Waist-Hip-Ratio, daily glucose average by 72-hour Continuous Glucose Monitoring System (CGMS), Hemoglobin A1c,

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Insulin Sensitivity and serum TNF-alpha levels. (C) Markers related to CVD: systolic and diastolic blood pressure, lipid profile (total cholesterol, HDL, triglycerides, LDL), plasma levels of fibrinogen, PAI-1, C-reactive Protein and serum Interleukin-6. We anticipate that this study will provide important new information that will have practical implications for both further scientific inquiry as well as clinical applications. Specifically: Identification of an acceptable intervention that promotes long-term weight loss and is associated with decrease in the morbidity and mortality associated with obesity and the metabolic syndrome will be an important development for public health. In relation to this suggestion, one of the important questions in dietary composition - energy regulation research currently is whether diets that are both high in fiber and low in GI are more beneficial that diets that are high in fiber without consideration of GI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLYCEMIC INDEX/GLYCEMIC LOAD AND BLOOD LIPIDS IN THE WHI Principal Investigator & Institution: Shikany, James M.; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Coronary heart disease (CHD) is the number one killer of postmenopausal women. Reduction in fat intake is typically recommended for the prevention and treatment of CHD. However, decreased fat intake is generally accompanied by an increase in carbohydrate intake, which may itself have undesirable effects on CHD risk factors. Recent evidence suggest that diets abundant in high-starch carbohydrates may have an adverse effect on blood glucose and insulin concentrations, resulting in alterations of blood lipids that may increase the risk of developing CHD. Glycemic index (GI) is a way of ranking carbohydrate-containing foods based on their postprandial blood glucose responses and is a measure of carbohydrate quality. Glycemic load (GL) is a measure that incorporates both the high dietary carbohydrates. There is mounting evidence from observational studies that high dietary GI and may adversely affect blood lipids, including increasing plasma triglyceride (TG) and reducing plasma high-density lipoprotein-cholesterol (HDL-C). The Women's Health Initiative (WHI) is a multi-faceted research program examining factors associated with disease risk in postmenopausal women. This study will utilize WHI participants to further investigate the associations of GI and GL with blood glucose, insulin, and lipids. The first aim of this study is to investigate the associations of dietary GI and GL with blood glucose, insulin, and lipid (total cholesterol, low-density lipopretein-cholesterol, HDL-C, and TG) concentrations in a cross-sectional analysis of 728 participants at baseline in the WHI Observational Study. The second aim is to quantify changes, over a one-year period, in dietary GI and GL in 973 participants randomized in the WHI lowfat Dietary Modification trial, and to determine the effects of those changes on blood glucose, insulin, and lipid concentrations. To meet these aims, the nutrient database of the WHI food frequency questionnaire (FFQ) will be expanded to include GI and GL, which are not currently reported. Existing WHI FFQs will then be reanalyzed to calculate each participant's mean dietary GI and GL. Existing blood glucose, insulin, and lipid data for these WHI participants will be used in the data analyses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF BIOMARKERS OF FATTY ACID INTAKE Principal Investigator & Institution: Campos, Hannia; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2003 Summary: Fatty acids in the blood and more recently in adipose tissue are widely used as biomarkers of fatty acid intake in individuals and populations. Feeding studies show that dietary fat composition markedly influences the fatty acid distribution of blood components and adipose tissue. Nevertheless, the relationships between specific fatty acid intake and their levels in blood and adipose tissue are scarce in epidemiologic studies. Technological advances in gas chromatography and fatty acid peak identification software now make it possible to study specific fatty acids in large population studies at a new level of sophistication. The overall goal of this project is to identify suitable blood biomarkers of specific fatty acid intake in 180 free-living subjects (90 men and 90 women). Over thirty-five fatty acids and their isomers will be identified in all study participants to: 1) Compare the ability of non-endogenously synthesized fatty acids in plasma, erythrocytes, whole blood and adipose tissue to reflect fatty acid intake, 2) Determine the distribution of individual fatty acids in these biological specimens and compare it to that of dietary fatty acid intake, and 3) Identify whether endogenously synthesized fatty acids can be suitable biomarkers of fatty acid intake. In secondary analyses we will explore specific fatty acids that may serve as indicators of food intake. The study subjects represent a subgroup of controls from an ongoing casecontrol study on gene-diet interactions and heart disease in Costa Rica. The composition of the diet in this population is similar to that in the United States (see preliminary results). Most importantly, all the fatty acids that are present in the biological samples from the United States can be identified in the Costa Rican samples. Our proposed study offers a unique opportunity to compare dietary intake, blood constituents and adipose tissue in the same population. Dietary assessment tools have been validated and all the biological specimens and dietary intake information have already been collected and adequately archived. This study will provide the most complete data set to validate the use of biochemical markers of specific fatty acid intake and improve our understanding of their role in carcinogenesis. Relapsed B cell lymphomas are incurable with conventional therapies except stem cell transplantation, a toxic treatment modality which salvages only 20-50% of patients with recurrent disease. Innovative new treatment approaches are therefore clearly necessary for this disease. This project will evaluate the feasibility, safety, toxicity, and efficacy of treating patients with relapsed follicular lymphomas with autologous CD8+ cytotoxic T lymphocytes (CTL) which have been genetically modified to express a chimeric T cell receptor recognizing the CD20 antigen present on B cell lymphomas. In Aim 1, we will perform preclinical studies transfecting autologous cytotoxic T lymphocytes obtained by apheresis with an scFvFc:zeta chimeric T cell receptor recognizing the CD20 antigen, clone and expand the transfected T cells, and document their specific cytotoxicity for CD20-expressing target cells. Comparative analyses will be performed using cytotoxic T cells transfected with alternative chimeric T cell receptors recognizing the CD19 and CD22 antigens. In Aim 2, we will assess the safety, feasibility, and toxicity of infusing ex-vivo expanded autologous CD8+ T cell clones expressing a CD20-specific scFvFc:zeta chimeric immunoreceptor into patients with relapsed follicular lymphoma in a small Phase I pilot trial. In Aim 3, we will monitor the trafficking of adoptively transferred CD20-specific CD8+ T cell clones to lymph nodes and other tumor sites and their persistence in vivo using serial quantitative Indium-111 gamma camera imaging, quantitative real time PCR and flow cytometric analyses of blood, bone marrow and lymph nodes. In Aim 4, we will rigorously assess the partial and complete response rates, remission durations,

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and adverse events induced by treatment with CTL bearing a CD20-specific chimeric T cell receptor in a Phase II trial planned to accrue 50 patients over 3 years. We anticipate that these studies will document the technical feasibility of this approach, the safety of administering genetically modified T cells and their ability to induce objective remissions in patients who have failed standard chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IGF-I: A NUTRITION-REGULATED TARGET IN PROSTATE CANCER Principal Investigator & Institution: Cohen, Pinchas; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 13-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): An energy-dense diet high in fat, refined sugar and providing excess calories relative to energy expenditure that is typical of Western diets has been associated with an increased risk of prostate cancer (CaP). Increased intake of lycopene-rich foods, such as cooked tomatoes, is associated with a decreased risk of CaP. Insulin-like growth factor-I (IGF-I) is a potent mitogen that has been implicated as a critical factor in the development of CaP. The pro-oncogenic role of IGF-1 has been extensively demonstrated in both in vitro studies and in animal models of cancer as well as in human epidemiological cohorts. Serum IGF-I is regulated by caloric intake in both human and animal models and it has been proposed that certain nutrients that may prevent CaP, in particular lycopene, also modulate IGF-I levels. Our preliminary data suggest that men at high risk for CaP who adopt a very low fat, high fiber diet under residential conditions, have reduced serum IGF-1 levels and their sera have decreased mitogenicity for CaP cells in vitro. We have also demonstrated that in CaP xenograftbearing SCID mice, a low-fat diet reduces serum IGF-I and leads to decreased mitogenicity of sera as well as to a marked reduction of tumor size and increased tumor apoptosis, when compared to mice fed a high fat, isocaloric diet. In addition, we studied TRAMP mice, a transgenic model of CaP (transgenic for SV40T antigen with a probasin promoter), and showed that decreasing caloric intake by 20% lowered serum IGF-I levels and decreased tumor incidence and severity. IGF-I infusion to these diet-restricted TRAMP mice restored serum IGF-I to ad-lib levels and caused an increase in tumor incidence similar to that seen in the ad-lib group. These studies led us to theorize that IGF-I is an important oncogenic circulating molecule, whose levels can be modulated by dietary composition. We hypothesize that that bioavailable IGF-I within the microenvironment of prostate epithelial cells in vitro is a major determinant of CaP development and progression. Therefore, modulation of IGF-I levels by nutritional factors may be an important potential therapeutic target for determination of CaP risk and progression. Our proposed studies will determine if dietary fat and/or lycopene regulate serum-bioavailable IGF-I in a manner that determine the development of CaP. Our specific aims are to: 1) Establish the effects of modulating dietary fat content from 42 to 12% on serum IGF-I and the concurrent progression of CaP in TRAMP mice and determine whether infusion of IGF-I is capable of reversing any reduction of tumor progression in the low-fat-fed group. 2) Examine the effects of genetically lowered serum IGF-I on the progression of CaP in LID mice, in which the liver IGF-I gene has been selectively deleted using Cre-Lox technology and in whom circulating IGF-I levels are 25% of normal, mated with TRAMP mice. 3) Determine if a high-fat diet modulates CaP progression and/or serum IGF-I in the LID-TRAMP model to assess the linkage between serum IGF-I, dietary fat and CaP. 4) Examine the relationships of dietary lycopene and fat in modulating CaP progression and/or serum IGF-I in the TRAMP and

40

Dietary Fat

LID/TRAMP models. We will determine the relative importance of free (bioavailable) IGF-I as compared to total IGF-I (which is bound to IGFBPs) in the development of CaP by developing new, specific assays for mouse free and total IGF-I, IGFBP-3 and IGFBP-1 Our studies will provide definitive information regarding the role of IGF-I as an important nutritionally regulated serum marker for CaP risk and progression and will allow the design of logical strategies to determine of the efficacy of dietary interventions in CaP prevention and treatment in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INCREASING AVAIL OF LOWFAT FOODS IN HIGH SCHOOLS Principal Investigator & Institution: French, Simone A.; Associate Professor; Epidemiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: High fat diets are widespread in the US and contribute to the development of cardiovascular disease. Adolescents are a key target group for intervention due to their high fat intake and because of the potential for long-term behavior change that would potentially impact chronic disease risk later in life. Vending machines, a la carte and fast food comprise an increasing share of the total food energy consumed by students at school. Yet these food sources have been virtually ignored in school-based nutrition intervention research. The proposed study will advance the research in this area by conducting a multi- component intervention that targets the total food environment in high schools. Modifications in the school vending machines, a la carte areas and fast food will be examined for their effects on dietary fat intake in adolescents. The present study will randomize 20 secondary schools to intervention or control for a two year period. The intervention consists of making more low fat foods available in the school a la carte areas, fast foods, and vending machines. A second intervention component will involve inviting a student group to promote low fat food choices on a school wide basis. The group will receive financial incentives from the study based on sales volume of low fat foods in the a la carte and vending machines. During the second intervention year, prices of low fat foods will be lowered to promote student purchase of low fat foods. Fat intake among a cross section of 1000 students (50 per school) will be measured at baseline, spring of intervention year 1 and spring of intervention year 2. Sales of low and high fat foods in vending machines and a la caret school food service areas will be continuously measured. It is hypothesized that dietary fat intake will decrease and sales of low fat foods will increase in intervention schools relative to control schools. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INCREASING SCHOOL SNACK BAR FRUIT AND VEGETABLE INTAKE Principal Investigator & Institution: Cullen, Karen W.; Assistant Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 31-JUL-2002 Summary: Inadequate intakes of fruit, juice, and vegetables (FJV) and high intakes of dietary fat are associated with increased risks for several cancers. Children's current FJV and fat intakes do not meet recommended guidelines and national data indicate a decline in children's fruit consumption through the school years. Previous school interventions targeted elementary schools where students only have the choice of the school lunch meal. When students move to middle schools and beyond, they have

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access to competitive foods at snack bars. These foods are usually high in fat and do not include many FJV. This research proposes to develop, implement, and evaluate an environmental intervention (increasing FJV availability and accessibility) and a cafeteria FJV marketing program in middle school cafeterias to increase FJV consumption, and to assess the effect of personal and social influences on who changes. Focus groups discussions will be conducted with middle school students, teachers, and school food service staff to design and evaluate the availability and marketing program. The intervention will be implemented in two phases following an initial two-month baseline monitoring period. First the availability and accessibility of FJV and low fat foods will be increased in the cafeteria snack bar for three months. This will be continued for another two months, adding the FJV marketing program. During the final two months, the intervention component will be withdrawn; observations will continue to see if school practices and snack bar food selections return to baseline. Weekly sales of FJV and low fat foods will be collected during this period to monitor intervention results. Consumption data will be obtained through daily observations of student lunches during the entire study period. This design will allow separate tests of the effect of increased FJV availability alone versus increased availability with a social marketing program, and assess personal and social environmental mechanisms of change. Successful dietary behavior change interventions in middle school cafeterias will promote the adoption of healthy cancer preventive dietary behaviors. Positive findings from this study should be applicable to middle schools where snack bars are available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE /DIET OF HISPANIC WOMEN W/ BREAST CAN Principal Investigator & Institution: Duarte-Gardea, Maria O.; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Background: Breast cancer is the most common cancer among women. A relationship has been hypothesized between insulin resistance and breast cancer. To our knowledge, no study has investigated the relationship among insulin resistance, energy and fat intake, and breast cancer in Hispanic women. The purpose of this project is to test the hypothesis that fasting insulin and other markers of insulin resistance, along with energy intake and dietary fat, will be significantly higher among Hispanic women diagnosed with breast cancer compared to those with no indication of cancer. Specific aims: Our aims are to compare the following characteristics among women with and without breast cancer: Aim 1) markers of insulin resistance and Aim 2) total energy and total fat intake. Aims 3) demographic, anthropometric, and reproductive, and Aim 4) lifestyle and dietary factors and their association with diagnosis of breast cancer. Design/Methods: A prospective case-control study of Hispanic women attending the University Breast Care Center at Texas Tech University Health Sciences Center at El Paso for routine breast examination will be conducted. Markers of insulin resistance including obesity, waist/hip ratio, blood pressure, acanthosis nigricans, fasting insulin, fasting glucose, and lipid profile will be performed in four hundred eligible participants. Subjects will complete a three-day food record to determine total energy and fat intake. Case and control groups will be formulated once the data are collected and after mammogram and pathology reports have been filed. The case group includes 100 subjects with breast cancer. Three controls (matched by age +/5 years) and menopausal status) for each case will be located from the pool of total participants. We will perform correlation and factor analyses to identify variables

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Dietary Fat

and/or factors which would best represent each of the four classes of independent variables as outlined in the specific aims section. We will then use logistic regression analysis to examine the relationship between the categorical response (diagnosed with and without breast cancer) with the set of independent variables identified above. The proposed work will advance the understanding of the associations of insulin resistance, diet and breast cancer in Hispanic women. Individual risk factors (anthropometric, health, reproductive, lifestyle and dietary) may be identified. There is a need for research that focuses on a comprehensive approach to insulin resistance, dietary lifestyle choices, and breast cancer and that emphasizes a fat-caloric intake-insulin resistance linkage. Such information is critical for the design of health education interventions that seek the adoption of healthy lifestyle in low income Hispanic population through community-based culturally relevant and tailored prevention programs, and public policy recommendations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN SENSITIVITY IN NON-OBESE SUBJECTS Principal Investigator & Institution: Sonko, Bakary J.; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: (taken from the application) The long-term aim of the investigator is to further better understanding of the role-of insulin resistance in body weight maintenance both in the obese and in the non-obese individual, ethnic differences and how its effects could be remedied. Obesity is wide spread in the U.S. and is known to be associated with many chronic diseases including diabetes. Hyperinsulinemia and insulin resistance normally precedes diabetes. The relationship between insulin resistance and body weight maintenance in the obese state is controversial. Insulin resistance is proposed to be an adaptive mechanism against further weight gain. However, 25 percent of non-obese individuals are insulin resistant, and could be considered predisposed to diabetes. To be both diabetic and insulin resistant would significantly increase one's risk to chronic diseases. This study will investigate whether non-obese individuals, with insulin resistance, are protected against obesity. The specific aims are: (a) to determine whether 24 hour-total and -dietary fat oxidation after consuming low and high fat maintenance meals, are higher in non-obese insulin resistant subjects compared to non-obese insulin sensitive subjects; (b) to determine the effect of 25 percent overfeeding on total and dietary fat oxidation in the two groups. Whole-body indirect calorimetry and 13C stable isotope ratio mass spectrometry will be used in this study. The topic of this study is important because it impacts a significant proportion of the U.S. population. The investigator does not have a major grant and the awarding of this grant will help him to generate the necessary data to allow him to apply for such a grant. This will be a significant burst to his career development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTERACTIVE TECHNOLOGIES TO MODIFY CANCER RISK BEHAVIORS Principal Investigator & Institution: Ahern, David K.; Abacus Technologies, Llc 1210 Pontiac Ave Cranston, Ri 02920

Management

Timing: Fiscal Year 2001; Project Start 08-SEP-2000; Project End 30-APR-2002 Summary: Smoking, poor diet and a sedentary lifestyle are among the chief preventable causes of cancer morbidity and mortality in the United States. Prior research has shown

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that physician counseling, prevention office systems, and computer-tailored health messages can all have an impact on common cancer risk behaviors (smoking, physical inactivity, high dietary fat). A critical question yet to be examined regarding the potential public health impact of computer technology is: If the full impact of computer technology is to be realized to reduce the national burden of cancer, then several challenges remain to be addressed including: Can interactive multimedia be integrated into the larger health care delivery system and then into the development and testing of a computerized set of tools that will be able to deliver theory-and evidence-based tailored messages to improve the dietary, physical activity and smoking patterns of lowincome patients in a primary care setting and to improve physician counseling for these behaviors. In the R25 portion of the project, we will bring together investigators with expertise in physician counseling and in creating tailored patient education materials for smoking cessation, physical activity and nutrition, and in applying technology to patient and physician education. The investigators will employ focus groups and in-depth interview methods with all stakeholders involved in the proposed system in addition to pilot tests of the intervention materials and instruments. Information gained from the above formative testing will enable the investigators to create a database of text and graphic messages that will serve as the "paper product" that will be translated to computer form and evaluated in the R44 portion of this project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIGHT PROGRESSION

DURING

DARKNESS

AND

BREAST

CANCER

Principal Investigator & Institution: Blask, David E.; Mary Imogene Bassett Hospital Cooperstown, Ny 13326 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (provided by applicant): The long-term goal of this research is to determine if light, present during darkness, is a risk factor for breast cancer progression. People in industrialized nations are being exposed to more artificial light during the night and the rate of breast cancer is increasing. The pineal gland hormone melatonin, which inhibits experimental human breast cancer growth, is produced during darkness; light present during darkness suppresses melatonin synthesis. The hypothesis to be tested is: Light, of the appropriate intensity, duration, timing and wavelength, present during darkness, stimulates breast cancer progression via melatonin suppression and a resultant disinhibition of tumor linoleic acid (LA) uptake and metabolism. The first aim is to measure the dose-response effects of exposure of nude female rats, bearing tissueisolated estrogen receptor (ER)+ and progesterone receptor (PgR)+ MCF-7 human breast cancer xenografts, to different intensities of white light during darkness, on melatonin suppression in relation to tumor growth, LA metabolism and the expression of related growth signal transduction molecules (i.e., ER and PgR, melatonin receptor and cAMP). The second aim is to determine the dose-response effects of exposure of nude rats bearing MCF-7 xenografis in comparison with those bearing ER/PgR- MDA-MB-23 1 human breast cancer xenografts to different intensities of white light on melatonin suppression in relation to tumor growth. The third aim is to determine whether melatonin replacement will prevent the stimulative of effects of white light exposure during darkness on tumor growth, LA metabolism and the expression of related tumor growth signal transduction molecules. The fourth aim will test the effects of the duration and timing of light exposure during darkness on tumor growth and growth signal transduction events. This research may lead to the elucidation of "light-at-night" in conjunction with dietary fat intake as a new risk factor for breast cancer progression and

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Dietary Fat

to novel preventative measures for lowering breast cancer risk by combining modifications of indoor lighting and dietary fat intake with melatonin supplementation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPID METABOLISM IN FAT CELLS Principal Investigator & Institution: Guo, Wen; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Medium chain fatty acid ingestion (MCFA) results in diminished fat storage in animals and humans, while similar intake of long chain fatty acids (LCFA) results in weight-gain. The goal of our project is to examine the cellular mechanisms underlying this phenomenon. Our hypothesis is that substitution of MCFA for LCFA will downregulate the expression of adipogenic proteins, lower the lipid storage capacity of adipose cells, facilitate fatty acid release from stored fat, and probably also reduce the capacity for differentiation of adipose cell precursors. The specific aims of this study focus on: 1) the metabolic fate of MCFA and how this is influenced by LCFA, glucose and insulin, 2) the effects of MCFA on fat storage and lipolysis, and on membrane lipid composition of sub-cellular components (plasma membrane, mitochondria, and endoplasmic reticulum); 3) the effects of MCFA on the expression of adipogenic proteins during the differentiation process; and 4) changes in fat cell function as a result of longterm MCFA dietary adaptation. An integrated approach will be used to characterize the metabolic end products of MCFA, to search for unidentified end products, and to explain the excess energy expenditure that results from MCFA treatment. We will identify and quantify, the major metabolic end products of fatty acids (lipids and CO2) by NMR. 13C isotope labeled substrates will be used in appropriate experiments. This greatly enhances the selectivity and sensitivity of NMR analysis. We will compare heat generation by cells adapted to MCFA or LCFA by measuring oxygen consumption and redox state; quantify the important metabolites (acetylCoA and acetylcarnitine) by HPLC, and analyze the fatty acid compositions by GLC. If significant changes in subcellular membrane composition are found as a result of MCFA treatment, subsequent effects on membrane structure and fluidity will be analyzed by solid state NMR. Other standard biochemical assays will be used for the measurement of ketone bodies, total triglycerides, cholesterol, DNA, protein, etc. The mRNA products of differentiationdependent adipogenic genes will be determined by Northern analysis. Fat cell morphology will be characterized by phase- contrast microscopy. Using this integrated approach, we anticipate developing important new information to help shed light on the molecular mechanisms of the control of obesity and obesity-related health disorders afforded through MCFA administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS Principal Investigator & Institution: Rudel, Lawrence L.; Professor; Pathology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 15-MAR-1993; Project End 30-JUN-2003 Summary: This Program Project application has as its central theme, the definition of the elements of lipoprotein metabolism related to coronary artery atherosclerosis. The preceding three decades have seen tremendous strides forward in our understanding of hyperlipoproteinemia and its relationship to coronary heart disease (CHD). However, many questions remain. In this Program Project, we are proposing to study the manner

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by which dietary fatty acids promote or protect against coronary artery atherosclerosis. We have developed data suggesting that certain dietary fatty acids promote or protect against coronary artery atherosclerosis. We will monitor the relative importance of LDL cholesterol concentration versus LDL composition as modified by dietary fatty acids by establish groups of African green monkeys with equivalent LDL cholesterol concentrations. In this case, the primary variable in atherosclerosis outcome is LDL composition, although the HDL cholesterol concentrations will also be measured and considered. We are proposing to examine the interactions of LDL with smooth muscle cells as they affect the production of arterial proteoglycans as a potential mechanism of atherogenesis. We have derived data showing diet-specific effects, i.e. LDL from mono unsaturated fat fed versus n-3 polyunsaturated fat-fed monkeys caused decreasing PG synthesis. In addition, we will investigate dietary fatty acid effects on a transgenic mouse model with markedly elevated plasma LDL cholesterol concentrations as a potential model in which to examine genetic aspects of diet-atherosclerosis-lipoprotein interactions. We will study the metabolic pathways through which plasma HDL levels are modified by dietary fat, and will evaluate the importance of dietary fat-induced modifications in HDL subpopulations in the atherosclerosis outcome. We will examine the pathways through which apoB-containing lipoproteins are assembled and secreted and how this process is regulated. We will examine the specific characteristics of apoA-I that contribute to HDL particle formation and stability. Finally, we will examine relationships between bile acids and the development of hyperlipoproteinemia, and define the physiologic and pathophysiologic implications. All of these efforts support the theme of the Program-to identify specific aspects in the regulation of lipoprotein metabolism as it affects coronary artery atherosclerosis. All of the programs are interrelated and yet contribute distinct types of basic information. Progress in these research areas will provide opportunities in the future for treatment of Coronary Heart Disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LOW FAT DIET AND BREAST CANCER RECURRENCE--OUTCOME TRIAL Principal Investigator & Institution: Nixon, Daniel W.; President; Institute for Cancer Prevention 1 Dana Rd Valhalla, Ny 10595 Timing: Fiscal Year 2001; Project Start 30-SEP-1988; Project End 31-DEC-2004 Summary: The Women's Intervention Nutrition Study (WINS) is an ongoing randomized multicenter clinical trial testing the hypothesis that dietary fat intake reduction as an adjuvant to standard breast cancer therapy will reduce disease recurrence and increase survival for women with localized breast cancer. The hypothesis is based on preclinical studies, epidemiological observations and plausible mediating mechanisms of action. Currently, 2096 women (on target to meet the 2,500 final accrual objective) have been randomized within one year of diagnosis to a fat intake reduction Intervention or a Control group. The dietary intervention, based on social cognitive theory, involves individualized counseling by nutritionists trained in motivational interviewing and includes goal assessment, tailored messages, selfmonitoring and cognitive restructuring. Dietary adherence, assessed with serial, unannounced telephone recalls has been maintained through three years with demonstrated significant (P