Chronic Obstructive Pulmonary Disease

CHRONIC OBSTRUCTIVE PULMONARY DISEASE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTE...

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CHRONIC

OBSTRUCTIVE PULMONARY DISEASE 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 2004 by ICON Group International, Inc. Copyright 2004 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., 1960Chronic Obstructive Pulmonary Disease: 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: 0-497-00252-3 1. Chronic Obstructive Pulmonary Disease-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 chronic obstructive pulmonary disease. 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 CHRONIC OBSTRUCTIVE PULMONARY DISEASE ...................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Chronic Obstructive Pulmonary Disease ..................................... 4 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 61 CHAPTER 2. NUTRITION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE .......................... 107 Overview.................................................................................................................................... 107 Finding Nutrition Studies on Chronic Obstructive Pulmonary Disease .................................. 107 Federal Resources on Nutrition ................................................................................................. 109 Additional Web Resources ......................................................................................................... 109 CHAPTER 3. ALTERNATIVE MEDICINE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE .... 111 Overview.................................................................................................................................... 111 National Center for Complementary and Alternative Medicine................................................ 111 Additional Web Resources ......................................................................................................... 128 General References ..................................................................................................................... 130 CHAPTER 4. DISSERTATIONS ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE ...................... 131 Overview.................................................................................................................................... 131 Dissertations on Chronic Obstructive Pulmonary Disease ....................................................... 131 Keeping Current ........................................................................................................................ 132 CHAPTER 5. BOOKS ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE .................................... 133 Overview.................................................................................................................................... 133 Book Summaries: Federal Agencies............................................................................................ 133 Book Summaries: Online Booksellers......................................................................................... 134 Chapters on Chronic Obstructive Pulmonary Disease .............................................................. 135 CHAPTER 6. MULTIMEDIA ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE ......................... 139 Overview.................................................................................................................................... 139 Video Recordings ....................................................................................................................... 139 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 143 Overview.................................................................................................................................... 143 NIH Guidelines.......................................................................................................................... 143 NIH Databases........................................................................................................................... 145 Other Commercial Databases..................................................................................................... 147 APPENDIX B. PATIENT RESOURCES ............................................................................................... 149 Overview.................................................................................................................................... 149 Patient Guideline Sources.......................................................................................................... 149 Finding Associations.................................................................................................................. 153 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 157 Overview.................................................................................................................................... 157 Preparation................................................................................................................................. 157 Finding a Local Medical Library................................................................................................ 157 Medical Libraries in the U.S. and Canada ................................................................................. 157 ONLINE GLOSSARIES................................................................................................................ 163 Online Dictionary Directories ................................................................................................... 165 CHRONIC OBSTRUCTIVE PULMONARY DISEASE DICTIONARY .............................. 167 INDEX .............................................................................................................................................. 227

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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 chronic obstructive pulmonary disease 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 chronic obstructive pulmonary disease, 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 chronic obstructive pulmonary disease, 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 chronic obstructive pulmonary disease. 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 chronic obstructive pulmonary disease, 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 chronic obstructive pulmonary disease. 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 CHRONIC PULMONARY DISEASE

OBSTRUCTIVE

Overview In this chapter, we will show you how to locate peer-reviewed references and studies on chronic obstructive pulmonary disease.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and chronic obstructive pulmonary disease, 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 “chronic obstructive pulmonary disease” (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: •

Effect of Cigar Smoking on the Risk of Cardiovascular Disease, Chronic Obstructive Pulmonary Disease, and Cancer in Men Source: New England Journal of Medicine. 340(23): 1773-1780. June 10, 1999. Summary: Sales of cigars in the United States have been increasing since 1993. Cigar smoking is a known risk factor for certain cancers and for chronic obstructive pulmonary disease (COPD). However, unlike the relation between cigarette smoking and cardiovascular disease, the association between cigar smoking and cardiovascular disease has not been clearly established. This article reports on a cohort study among 17,774 men, 30 to 85 years of age at base line (from 1964 to 1973) who were enrolled in

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Chronic Obstructive Pulmonary Disease

the Kaiser Permanente health plan and who reported that they had never smoked cigarettes and did not currently smoke a pipe. Those who smoked cigars (1546 men) and those who did not (16,228) were followed from 1971 through the end of 1995 for a first hospitalization for or death from a major cardiovascular disease or COPD, and through the end of 1996 for a diagnosis of cancer. In multivariate analyses, cigar smokers, as compared with nonsmokers, were at higher risk for coronary heart disease, COPD, and cancers of the upper aerodigestive tract and lung, with evidence of dose response effects. There appeared to be a synergistic relationship between cigar smoking and alcohol consumption with respect to the risk of oropharyngeal cancers and cancers of the upper aerodigestive tract. The authors conclude that, independent of other risk factors, regular cigar smoking can increase the risk of coronary heart disease, COPD, and cancers of the upper aerodigestive tract and lung. 4 tables. 47 references. (AA-M). •

Chronic Obstructive Pulmonary Disease and Cognitive Impairment in the Elderly Source: International Psychogeriatrics. 8(1): 113-125. 1996. Summary: This cross-sectional epidemiological study in Lieto, Finland, compared 61 men and 21 women with chronic obstructive pulmonary disease (COPD) with agedand sex-matched people from the same community to analyze the associations between COPD, cognitive performance, and occurrence of dementia. The cognitive assessment was based on the Mini-Mental State Examination (MMSE), previous clinical documents, and an assessment made by the research nurse after she had interviewed and tested each patient. These three measures revealed no differences between COPD patients and the age-matched people, and MMSE subtest scores did not differ significantly between these two groups of participants. The findings suggest that the relative contribution of COPD to the occurrence of cognitive impairment and dementia in older people may be none or minimal at the community level. 31 references. (AA-M).

Federally Funded Research on Chronic Obstructive Pulmonary Disease The U.S. Government supports a variety of research studies relating to chronic obstructive pulmonary disease. 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 chronic obstructive pulmonary disease. 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 chronic obstructive pulmonary disease. The following is typical of the type of information found when searching the CRISP database for chronic obstructive pulmonary disease:

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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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Project Title: A FUNCTIONAL GENOMICS HEART & LUNG DEVELOP. PROGRAM Principal Investigator & Institution: Hoffman, Eric P.; A James Clark Professor of Pediatrics, b; Children's Research Institute Washington, D.C., Dc 20010 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: Drs. Eric Hoffman and Dietrich Stephan (whose primary interests are focused on muscle disease and leukemia) are PI and Co-PI on the Program's Expression Array Core and have extensive experience with all aspects of array use and data analysis. They have established collaborations with Dr. Michael Bitmer, Dr. Yidony Chen and the entire NHGRI array community. As a post-doctoral fellow in the laboratory of Dr. Jeffery Trent (member of this Program's External Advisory Committee), and a pioneer in DNA microarray technology, Dr. Stephan developed several alternative approaches to label total RNA for efficient signal detection under varying circumstances which have become the standard protocol used at NHGRI and has become a quite robust and reliable system for detecting signals over several orders of magnitude. In addition to building and using 7K expression arrays, Dr. Stephan was the first at NHGRI to develop genomic DNA microarray systems. Dr. Hoffman's laboratory is particularly interested in systematic assessments of the sensitivity and specificity of the Affymetrix vs. cDNA array approaches, and shows preliminary data pointing out the importance of redundant measurements, and correlative studies. Indeed, the proposed systematic comparison of the Affymetrix and cDNA array experimental platforms should be the first of this type of quality control of expression array data, and should prove highly valuable to both Program investigations and the research community at large. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A PROTEOMICS APPROACH IN THE STUDY OF NOVEL COPD MARKERS Principal Investigator & Institution: Djukanovic, Ratko; University of Southampton Highfield Southampton, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): COPD is a major health problem worldwide, but our level of understanding of its mechanisms, when compared to the other important airway disease, asthma, is relatively poor. COPD is a disease which progresses at a slow rate, which makes it very difficult to study its natural history and the impact of any therapeutic intervention. For all these reasons, it is vitally important to discover biomarkers that are elective for COPD, i.e., they are not general markers of lung inflammation and remodeling, and are prognostic for the rate of clinical deterioration. A number of non-invasive markers have been studied to date; to our knowledge, none of these have fulfilled the above criteria. As with other inflammatory lung diseases, a host of inflammatory and remodeling processes are involved in the pathogenesis of COPD, which render a singlemarker approach unlikely to succeed. We hypothesize that a number of proteins or protein isoforms are differentially expressed in the airway lining fluid in COPD and that these reflect the chronic pathology of COPD, rather than the chronic and acute effects of smoking. We propose to test this hypothesis using a proteomics approach as our primary, unbiased filter, to identify a set of 15 differentially expressed proteins (DEPs) that are present in a group of meticulously characterized subjects with COPD, but not present in those who have no evidence of lung damage despite an equivalent smoking history. Our programme is staged in a way to optimize the use of the state-of-the-art proteomics technology and precious archival samples

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collected over up to 17 years at the University of Nebraska and more recently in Southampton. Because we believe that patterns (groups) of biomarkers are more strongly related to COPD, we will apply multivariate analyses to identify the DEPs, which will thus become Early Candidate COPD-Selective Biomarkers. We will then develop antibodies against these in order to provide reagents for immunoassays. The latter will be applied to potentially as many as 480 subjects who have COPD, chronic severe asthma, or are healthy smokers or non-smokers. This will allow us to follow a logical sequence of further selection of biomarkers with respect to their selectivity for COPD, presence in early stages of smoke-induced lung damage and their prognostic value in terms of clinical deterioration and decline in lung function. Finally, applying the antibodies to archival lung tissue samples we will be able to localize the COPDselective proteins to the airway and alveoli, adding valuable knowledge to our understanding of COPD mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A ENHANCEMENT

RANDOMIZED

TRIAL

OF

HOME

SELF-EFFICACY

Principal Investigator & Institution: Jerant, Anthony F.; Family and Community Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Background: Key reasons for the "quality chasm" between current and ideal chronic illness care are that our health care system is insensitive to patient preferences, provider-driven, and disease-focused. By contrast, a common goal among proposed patient-centered care models is to foster continuous healing relationships between patients and the health care system. Such relationships allow patients to receive care over time via a variety of communication media, rather than just via episodic office visits. Home health care can foster such relationships and improve outcomes for patients with a variety of conditions. Home interventions may be particularly useful in caring for the growing number of people with chronic illnesses and accompanying functional limitations that might limit their access to communitybased interventions. However, trials comparing the effectiveness and cost-effectiveness of the wide array of home care models are limited, and the mechanisms that underlie their effectiveness remain unclear. Aims/Hypotheses: This study will address these research gaps. The study hypotheses are: a) Each of three home interventions will result in improvements in patient self-efficacy, adherence to care, and health-related quality of life (HRQOL) compared with usual care but will not differ statistically; b) From the payer's perspective, all the interventions will be cost saving compared with usual care, and a standard telephone intervention will be the most cost saving; and c) Self-efficacy will improve temporally before adherence to care and HRQOL. Methods: This will be a randomized controlled study of four groups, comparing the effectiveness and incremental cost-effectiveness of three different home-based care models and usual care in improving chronic illness outcomes. The chronic illnesses targeted will be arthritis, asthma, chronic obstructive pulmonary disease, congestive heart failure, depression, and diabetes mellitus. Trained laypersons will deliver the interventions, a self efficacy enhancement program (vs. usual care). The home care delivery media in the models will be in person visits, videophone calls, and standard telephone calls. The primary outcomes will be HRQOL and costs. Implications: Better understanding of the mechanisms of effectiveness of home care will facilitate the development of optimal

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home interventions. The findings will help policymakers, payers, and providers identify which interventions to implement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADMINISTRATIVE/EDUCATION IMMUNITY PGA

CENTER

FOR

INNATE

Principal Investigator & Institution: Weiss, Scott T.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Haponik, Edward F.; Professor of Internal Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Clinical Core will serve as the coordinating center for patient recruitment, specimen procurement and data base management. It is the mission of this Core to identify and provide disease-specific candidate genes from patients with such clinical disorders as acute lung injury, COPD, cystic fibrosis, asthma, pulmonary hypertension, pulmonary fibrosis, ischemic heart failure and both lung and cardiac transplant rejection. This core will also be responsible for the establishment of a Cardiopulmonary Tissue Repository that will maintain an archive of cryopreserved tissues and maintain an accurate data base of patient demographic and clinical data for correlation with biological end points produced by cDNA microarray. Following patient consent and registration, tissue samples and peripheral blood are delivered to the Core laboratory. The freezing facility will also serve as a repository for cyropreserved human lung and cardiac specimens. The Core Investigators will meet regularly to review all diagnostic materials on each specimen procured including histochemical stains and biopsies in order to determine a precise diagnosis and relevant demographic and clinical data for entry into the Project's data base which will include critical variables for the analysis of the biological data obtained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Scott, Alan F.; Director; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The use of single nucleotide polymorphisms (SNPs) is likely to become a major tool for the discovery of genetic linkage and disease association in the coming decade. New technologies currently entering the laboratory will allow investigators to perform high throughput studies that, until now, were impossible. The Genotyping Core proposes to locate SNPs in genes with demonstrated or presumed relevance to human cardiopulmonary disease. We will select 20 candidate genes for SNP analysis per year in airway diseases (cystic fibrosis, chronic obstructive pulmonary disease, and asthma) and selected from comparisons of our expression profiling analysis in human and animal models of human disease. We anticipate three to five SNPs per gene, which we can then evaluate in well-defined patient populations. We hypothesize SNP may explain phenotypic differences in carefully defined disease severity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE-EDUCATION Principal Investigator & Institution: Goldstein, Allan L.; Biochem and Molecular Biology; George Washington University 2121 I St Nw Washington, Dc 20052 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Education Core will address an important focus of this Program. Attainment of goals should be ensured by the hierarchical nature of the Program design, emphasis on educational components, timed data release to the public, and history of interactions between many of the individual investigators. The close affiliation of the

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CNMC Research Center for Genetic Medicine with George Washington University, TIGR, and the NIH will also afford the use of pre-existing resources. This Program relies heavily on the web-based educational paradigms developed by Program member Stephen Engraft, who has developed the Frontiers in Genetics web-based lecture and CME course series (see www.frontiersingenetics.com). Development of the proposed web-based educational programs and data repositories will be facilitated by its multidepartmental nature. Our Program will help catalyze other broad- based institutional efforts (e.g. through mini symposia and CME programs based at Johns Hopkins. Finally, through the leadership roles of Hopkins co-investigators within major national specialty societies, delineation of a spectrum of CME activities will be pursued (e.g. at the international meetings of the American Thoracic Society, the American Heart Association and the American College of Chest Physicians, and at the regional meetings of the American Federation for Medical Research. These latter activities generate new collaborators at other medical centers who will be prepared to query the Hopkins database. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BALANCING HOPE & TRUTH-TELLING FOR PATIENTS WITH CA/COPD Principal Investigator & Institution: Curtis, J Randall.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2005 Summary: (provided by investigator): Patients with terminal or life-limiting illness report a strong need to maintain hope that they will overcome their illness while, at the same time, they desire full disclosure about their diagnosis and prognosis. These two goals, to maintain hope and know the truth about one's prognosis for survival and quality of life, are often difficult for clinicians to reconcile. Experts in end-of-life care call for clinicians to redirect patients' hope from hope for cure toward hope for quality of life and quality of dying when prognosis is poor. However, there are no data that help clinicians know how to offer hope and simultaneously provide accurate prognostic information to dying patients. This proposed study would examine the perspectives of patients with terminal cancer and chronic obstructive pulmonary disease (COPD), their families, and their health care providers concerning the often-perceived conflict between the need for hope and the need for truthful information about prognoses. We will conduct a series of open-ended interviews with patients, family members, nurses, and physicians. Interviews will be conducted by trained qualitative researchers serially over a twelve-month period and will be analyzed by the investigators using the principles of grounded theory. In addition, quantitative surveys will be conducted with participants at the same time points to provide descriptive information and permit construct validation of the qualitative data. Participants will be selected to represent culturally and ethnically diverse perspectives and analyses will incorporate this diversity. Finally, the findings will be presented to focus groups to assess the trustworthiness of the analyses and improve generalizability of the findings. The overall objective of this study is to develop strategies for clinicians to use throughout the course of a life-limiting disease to support patients in their dual needs for hope and truthfulness. These strategies will be described and translated into interventions targeting nurses, physicians, and teams who provide care for patients with cancer, COPD, and other lifelimiting diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BDNF IN PLASTICITY OF CHEMOAFFERENT PATHWAY Principal Investigator & Institution: Katz, David M.; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-DEC-2006 Summary: (provided by applicant): The aim of the proposed research is to define the role of Brain-Derived Neurotrophic Factor (BDNF) in activity-dependent plasticity in the developing chemoafferent pathway. Chemoafferent neurons are the link between peripheral chemoreceptors and the brainstem, and thereby play a pivotal role in cardiorespiratory homeostasis. At birth, chemoafferent reflexes are immature, and perturbations in oxygen availability can derange postnatal development of cardiorespiratory responses to acute hypoxia. However, mechanisms that underlie chemoreflex development and plasticity are largely undefined. This proposal is based on our recent discoveries that 1) Chemoafferent neurons in the newborn rat nodosepetrosal ganglion complex (NPG) express high levels of BDNF messenger RNA and protein, 2) BDNF protein is released from NPG neurons in response to patterned electrical stimulation in vitro, and 3) BDNF acutely inhibits glutamatergic AMPA receptors in second-order relay neurons in the nucleus tractus solitarius (nTS), the primary site of chemoafferent projections to the brainstem. Together, these data indicate a new role for BDNF as a modulator of excitatory synaptic transmission between primary chemoafferent neurons and second-order relay neurons in nTS. In view of increasing evidence that BDNF plays a critical role in long-term synaptic plasticity elsewhere in the brain, we hypothesize that BDNF plays a similar role at chemoafferent synapses in nTS. Moreover, based on our preliminary data, we hypothesize that BDNF signaling in nTS is regulated by changes in oxygen availability, and thereby contributes to derangements in chemoreflex function following chronic sustained or intermittent hypoxia. Therefore, the proposed research is designed to further define mechanisms of BDNF expression and release in chemoafferent neurons after birth, including the role of chronic sustained and intermittent hypoxia, in vivo and in vitro. In addition, we will characterize postsynaptic effects of BDNF on developing nTS neurons, including regulation of transmitter receptor expression and dendritic growth. Moreover, we will determine the role of BDNF in functional plasticity in vivo by analyzing development of peripheral chemoreflexes in transgenic mice in which BDNF signaling is disrupted selectively after birth. By defining mechanisms of activity-dependent plasticity in the PG and nTS, the proposed research may shed light on cellular and molecular mechanisms relevant to understanding and improved management of hypoventilation and apnea syndromes in neonates and infants, as well as mechanisms that contribute to altered cardiorespiratory control in adult obstructive sleep apnea and chronic obstructive pulmonary disease. Moreover, it is hoped that elucidating development of this system will, in turn, create a model of neurotrophin function applicable to the nervous system as a whole. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INSOMNIA

BEHAVIORAL

TREATMENT

FOR

COMORBID

GERIATRIC

Principal Investigator & Institution: Rybarczyk, Bruce D.; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: Description (adapted from the investigator's abstract): This is a revised application to test the efficacy of an empirically based cognitive-behavioral intervention

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for older adults with insomnia and co-morbid chronic illness recruited from an HMO population. The primary objective of the study will be to compare the efficacy of behavioral treatments for insomnia among patients with 3 common age-related chronic illnesses: osteo-arthritis (OA), chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) because exceptionally high rates of co-morbid insomnia have been found in the 3 groups. A second major objective is to determine whether an effective behavioral treatment can diminish the well-established effects of insomnia on quality of life among those with chronic illness. The proposed study will include random assignment of 3 groups of 55 HMO patients 55 years or older with OA, COPD and CAD and co-morbid insomnia to an 8-week cognitive-behavioral treatment class or placebo control class. The behavioral intervention will be empirically based with both cognitive-behavioral and relaxation approaches. The placebo control group will be a wellness/stress management class. Outcomes will be assessed at 4, 8, and 12 months post treatment follow-up intervals. Sleep quantity and quality will be evaluated using polysomnography, actigraphy and self report measures. Quality of life, functional status and mood will also be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOINFOMATICS CENTER FOR INNATE IMMUNITY PGA Principal Investigator & Institution: Klimecki, Walter T.; Associate Research Scientist; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify

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SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOINFORMATICS CENTER FOR INNATE IMMUNITY PGA Principal Investigator & Institution: Lazarus, Ross; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design,

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data handling and data analysis in genetic epidemiology; and ethical issues in population genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMARKERS OF OXIDATIVE STRESS AND INFLAMMATION IN COPD Principal Investigator & Institution: Macnee, William; University of Edinburgh Edinburgh Eh8 9Yl, Scotland Edinburgh, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a disease with a major unmet medical need, for which at present there is no effective treatment that will halt the decline in lung function. Development of new therapies is hampered by the lack of well defined clinical biomarkers to both characterize patients and assess drug efficacy. Oxidative stress and the associated inflammatory responses in the lungs are key elements in the pathogenesis of COPD. However, there have been no longitudinal studies to assess the utility of representative markers of oxidative stress and inflammation as biomarkers of disease severity and hence their potential as surrogate endpoints for assessment of the effectiveness of new therapeutic agents. The purpose of this project is to identify and characterize candidate markers of oxidative stress and inflammation in both cross sectional and longitudinal studies. The proposed biomarkers for these studies are the lipid peroxidation products 4-hydroxy-2-nonenal, F2alpha-isoprostanes, and cytokines such as interleukin (IL) IL-8, IL-6, IL-1, tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor in a well characterized cohort of COPD patients in both cross sectional and longitudinal studies. A further aim is to relate the levels of these markers of oxidative stress to inflammatory mediators and differential cell counts in induced sputum. In addition, a population of COPD patients will be characterized according to the levels of surrogate markers of airway inflammation and oxidative stress, which will be related to disease severity and to the clinical phenotype of COPD. Sophisticated techniques such gas chromatography/mass spectrometry (GC/MS) will be used to measure specific and stable lipid peroxidation products in peripheral blood, induced sputum and exhaled breath condensate. Moreover, mindful of the possibility that no single molecule will be a biomarker which is applicable to all patients with COPD, metabonomic and genomic technologies will be exploited to assess a spectrum of potential biomarkers, thus generating a 'finger print' characteristic of the disease. Such information will allow the identification of novel biomarkers and the fingerprints themselves may represent a mechanism to stratify COPD patients and allow the assessment of novel therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHALLENGING LIFE EVENTS IN OLDER PERSONS Principal Investigator & Institution: Daaleman, Timothy P.; Family Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Timothy P. Daaleman, DO, is a family physician researcher with expertise in examining the influence of religious and spiritual variables in healthcare settings. This application will provide a period of mentored training comprised of: a research practicum within the Center on Aging at the University of Kansas Medical Center (KUMC); coursework in the Masters in Public Health (MPH) program and at the University of Kansas in Lawrence; and a research project to test a

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theoretical model of the relationship between spirituality and patient conceptualization of death and dying in a population of community-dwelling elders with serious illness. The plan outlines the training and research experience he will require, in order to develop and launch a fully independent research career that will focus on understanding and improving the dying process and end-of-life care among elders in the United States. Career Development Plan: Course work from MPH program forms the core portion of the didactic training period and will be complimented by practical training in study design, subject recruitment, data collection and analysis, and project management within the KUMC Center on Aging. Research Program: The SUPPORT trial not only awakened American medicine to reexamine the way it cares for seriously ill and dying patients, but also has indirectly promoted a rapprochement among the realms of spirituality, religion, and the practice of medicine. An understanding of the psychological, social, cultural, and now spiritual elements and processes that are involved in the composition of death and dying attitudes holds promise in comprehending and potentially improving the difficult transition that older patients make from serious illness to dying. The overall objective of this research project is to describe and understand the determinants of elders attitudes toward serious illness, death, the dying process, and discussions of advance care planning. Both rural and urban primary care physicians (N=10) who have been members of the Kansas Hartford Geriatric Project, and older community-dwelling patients with serious illness from their practices (N=270), will participate in three phases of the study: a cross-sectional survey, a prospective, longitudinal cohort study, and qualitative semi-structured interviews. The primary aim is to determine the social, psychological, spiritual, and cultural influences that comprise attitudes towards death and the dying process in older persons. Our hypothesis is that patient spirituality is a significant explanatory factor in death attitudes after accounting for multiple covariates, i.e. social support, mental health status. Secondary aims include learning how a baseline measure of patient spirituality predicts future death attitudes and discussions of advance care planning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINE BLOCKADE TO PRESERVE LUNG DEVELOPMENT Principal Investigator & Institution: Auten, Richard L.; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Chronic lung disease in prematurity (CLD) may affect as many as 50% of very low birthweight newborns. CLD confers added risk for abnormal neurodevelopmental outcome. Inflammation in response to adequate antioxidant defenses in premature newborns is central to the pathophysiology of lung injury leading to CLD. Present therapy includes glucocorticoids which may adversely affect lung, somatic and central nervous system development.,. Targeted immunotherapy blocking early inflammatory-induced lung injury may prevent the development of CLD and avoid adverse steroid effects. Our hypothesis is that blocking leukocyte influx and/of function will prevent chronic lung disease in the hyperoxia-exposed rodent model. The proposed studies will use hyperoxia-exposed newborn rodents to study the mechanisms of inflammatory effects on lung development in response to serve oxidant stress, as a model of CLD. Neutrophil and macrophage influx/function will be modified by using specific anti- chemokine antibodies and chemokine receptor antagonists. The contribution of key neutrophil functions will e studied in gene knockout mice lacking these functions. Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during

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initiation of hyperoxia-induced lung injury. Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury. Aim 2 will determine the specific contributions of leukocyte influx/function to DNA damage, growth arrest, and pathologic apoptosis, which contribute to abnormal alveolar development. Aim 3 will determine whether blockade of leukocyte function can safely preserve normal alveolar development during recovery from severe oxidant stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOPREVENTION OF LUNG CARCINOGENESIS USING GREEN TEA Principal Investigator & Institution: Hakim, Iman A.; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2003; Project Start 07-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant) Many laboratory studies have shown an inhibitory action of green tea or the polyphenolic fraction of green tea in animal models of lung carcinogenesis. Thus, the role of tea drinking as a potential inhibitor of carcinogenesis merits careful evaluation. In our attempt at translating the abundant pre-clinical information and epidemiological data to the human population, we are proposing a Phase IIb 3-arm randomized, placebo controlled, double blinded green tea intervention trial among former smokers with chronic obstructive pulmonary disease (COPD) and >= 40 pack-years of smoking history. This population is targeted because they have been identified as having a high prevalence of premalignant dysplasia. Subjects will be randomly assigned to consume daily for six months either a standardized green tea (GT) beverage, or a defined green tea polyphenol (GTP) extract in capsule form, or placebo preparations. The hypotheses to be tested in the proposed research are 1) high consumption of GT or GTP can protect against cellular oxidative damage and 2) high consumption of GT or GTP can modulate the expression of genes involved in proliferation and apoptosis in a population at elevated risk of lung cancer. The primary endpoints will be improvement in markers of oxidative damage in DNA, lipids, and proteins (levels of 8-OHdG, 8-epi-PGF2, MDA, di-tyrosine, and catalase and glutathione peroxidase activities). The secondary endpoints will be exploratory to assess changes in the gene expression of biomarkers of proliferation (EGFR, PCNA, JUN, FOS, Ki-67) and apoptosis (bcl-2, caspase-3) in induced sputum, in addition, we will seek to determine if there are differences in adherence between the green tea preparation groups. We believe that a program of nutritional intervention by realistic dietary modifications that are effective, safe, and acceptable should be the cornerstone of lung cancer prevention strategy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC LOCALIZATION

OBSTRUCTIVE

PULMONARY

DISEASE

GENE

Principal Investigator & Institution: Hasstedt, Sandra J.; Associate Professor; Institute of Human Genetics; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Applicant's Abstract): Chronic obstructive pulmonary disease (COPD) is a slowly progressive disorder characterized by airways obstruction that lasts for at least several months. The two major causes of COPD are chronic bronchitis and emphysema. Either disorder may occur with or without airways obstruction, but airways obstruction

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causes impairment of lung function leading to disability and death. COPD is a major health problem in the United States and throughout the world, consistently ranking among the most common causes of death in the United States. Cigarette smoking is the primary environmental factor that increases the risk of COPD, but other environmental factors have also been implicated. However, despite a well-established role, environmental factors alone do not cause COPD. Symptomatic COPD develops in only 10-20 percent of heavy cigarette smokers, probably those with a genetic susceptibility, although common COPD susceptibility genes have yet to be identified. This project proposes a single specific aim: to localize, within the genome, a COPD susceptibility gene. The strategy proposed is to apply statistical linkage analysis to family data. Pulmonary measurements have already been collected on 159 members of 16 pedigrees and evidence supporting a COPD susceptibility gene in these pedigrees has been obtained from segregation analysis. Each of 11,995 genetic markers, which have already been genotyped on pedigree members, will be tested for evidence of linkage to the inferred COPD susceptibility gene. Evidence of linkage to one or more genetic markers will identify genomic locations of COPD susceptibility genes. The high density of markers will allow fine-mapping of the gene. Successful completion of this gene localization project is the necessary prerequisite for a project to identify and characterize a COPD susceptibility gene. Identifying a gene that when mutated increases the risk of COPD may increase understanding of pulmonary function, as well as allowing genecarriers to be identified and made aware of their susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLARA CELLS, THEIR SECRETIONS IN LUNG IMMUNOREGULATION Principal Investigator & Institution: Stripp, Barry R.; Associate Professor; Environ & Occupational Health; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Even though cytokine production by cells of the immune system can significantly impact epithelial cell function, little is known of reciprocal roles for epithelial cells in regulation of the immune system. This is a significant issue when trying to understand the complex series of events that lead to deteriorating lung function among individuals with chronic inflammatory and/or immunological lung diseases such as COPD and asthma. There is a growing recognition that the conducting airway epithelium is dynamic in its function and that chronic lung disease results in predictable changes to epithelial cells. Among these changes are alterations in nonciliated airway epithelial cell function, for which reduced abundance of Clara cell secretory protein (CCSP) serves as a biomarker. Whether changes to Clara cells are a cause or a nonciliated airway epithelial cells contribute to exacerbation of lung disease and a continuing decline in lung function. Our recent studies in CCSP null mice (CCSP-/-) demonstrate that Clara cells fulfill important roles in defense against environmental agents in addition to serving critical immunoregulatory functions. Central to this proposal is the observation that CCSP-/- mice have elevated local production of IgA. Moreover, expression of IgA is dramatically up regulated following in vivo endotoxin exposure of CCSP-/- but not wild type mice, demonstrating fundamental differences in B-cell responsiveness with CCSP deficiency. We hypothesize that CCSP functions to suppress the immune system through either directly or indirectly regulating local B-cell function, and that these changes in B-cell function impact innate mucosal defense. If correct, changes in Clara cell function may lead to hyperstimulation

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of the local immune response which, although beneficial with respect to the acute clearance of colonizing microorganisms, could exacerbate airway disease and dysfunction. Aims will address four specific aspects of altered lung function that accompanies CCSP deficiency: 1) does CCSP deficiency result in altered innate and/or adaptive immunity, 2) are changes in lung immunoregulation and innate defense directly related to loss of CCSP, 3) are differences in innate defense with CCSP deficiency directly related to altered B-and/or T-cell function, and 4) which cell types are most sensitive to CCSP-dependent alterations in endotoxin signaling. By addressing these aims we will define mechanisms by which CCSP deficiency leads to altered immunoregulation within the lung. This knowledge may help in the development of strategies to block inappropriate immunological responses that lead to deteriorating lung function among individuals with chronic lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL CENTER IN COPD Principal Investigator & Institution: Bailey, William C.; Professor and Director; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a serious public health problem responsible for more than 500, 000 hospitalizations, 100,000 deaths, and $15 billion in direct costs of medical care in the United States each year. We propose to form a collaborative COPD CRN Clinical Center at the University of Alabama at Birmingham (UAB) and the Birmingham Veterans Affairs Medical Center (BVAMC). The UAB/BVAMC Clinical Center will be headed by, Drs. William C. Bailey and J. Allen D. Cooper. The proposed investigators and their research staff have extensive experience in recruitment and retention for clinical trials, as well as study design and implementation. The collaborative effort between UAB and the BVAMC will allow us to quickly and efficiently recruit large numbers of COPD patients for clinical research studies. In addition, the UAB/BVAMC COPD Clinical Center will have access to a large network of experts at the University of Alabama at Birmingham who can assist in the design and implementation of clinical trials. The UAB/BVAMC Clinical Center proposes two studies aimed at enhancing treatment for moderate-to severe COPD. The first study will examine measures of inflammation and responsiveness to bronchodilator challenge, responsiveness to systemic steroid treatment, and responsiveness to inhaled steroid treatment. This study may provide a new method for identifying subgroups of COPD patients who are most likely to respond to inhaled corticosteroids. The second project will examine the causes of poor responsiveness to the pneumococcal vaccine with the long term goal of using this information to reduce pneumococcal infections and related exacerbations in COPD patients. The UAB/BVAMC Clinical Center also proposes a Clinical Research Skills Training Core. Dr. J. Allen D. Cooper, the Director for fellowship training in Pulmonary and Critical Care Medicine at UAB, will head this core. Trainees will be funded for a total of two years and will be required to enroll in one of the UAB K30 Clinical Research Curriculum Development Award components (either the Clinical Research Training Program or the Master's of Science in Public Health in Clinical Research). Trainees will also receive funding for a pilot project, which will be developed and conducted under the supervision of the Training Core Investigators. These Investigators have expertise in COPD, Clinical Research and Study Design, Behavioral Science, Epidemiology, and Statistics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL CENTER-COPD CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Scharf, Steven M.; Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Chronic obstructive pulmonary disease is a major problem worldwide with increasing prevalence and morbidity/mortality. Current therapy is based on smoking cessation, maximizing lung function, treating infection and rehabilitation. The increase in knowledge about basic disease mechanisms affords the opportunity to explore new methods for treating this disorder. We propose the development of a clinical center at the University of Maryland to participate in the NIH COPD Clinical Research Network. In addition to describing the patient population and recruitment strategies, we present 2 model proposals for consideration by the network. The first proposal relies on recent findings that there is a strong inflammatory component in patients with end-stage COPD which may lead to weight loss, muscle wasting and increased mortality. A key inflammatory cytokine is tumor necrosis factor alpha (TNFalpha). We propose evaluating the effects of anti-TNFalpha therapy (inflixamab) in moderate to severe COPD patients in a 3-arm randomized blinded trial. Patients will receive 26 weeks of infliximab, 24 weeks inflixamab/12 weeks' placebo or 36 weeks of placebo treatment. Our primary outcome will be 6 minute walking distance, a measure of exercise tolerance. A number of secondary variables including proinflammatory cytokines in sputum and blood, pulmonary physiological and metabolic outcomes, body composition and quality of life (QOL) indices will be measured as well. The second proposal is on the use of inhaled steroids in COPD. Results from previous trials have in general been disappointing. However, there are likely to be subsets of patients who respond. We predict that patients with a prominent airway inflammatory component to their disease will be likely to respond to inhaled steroids and would be candidates for long-term treatment. We will determine if the sputum level of proinflamamtory cytokines is predictive of the response to steroid inhalers in COPD. We will determine if the presence of a single nucleotide substitution in the glucocorticoid receptor has a negative impact on the response. Outcomes from this randomized clinical trial will be gauged in terms of health related QOL. In addition to presenting these formal proposals, we have developed several concept proposals. We have also offered the development of a health cost utilization core for the COPD CRN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COGNITIVE EFFECTS OF LUNG VOLUME REDUCTION SURGERY Principal Investigator & Institution: Kozora, Elizabeth; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: The primary goal of this study is to examine the neuropsychological functioning of emphysema patients undergoing lung volume reduction surgery (MT+LVRS) compared to medical therapy alone (MT). The study will include patients at two clinical sites for the National Emphysema Treatment Trial (NETT). Enhancements of ventilation and functional capacity are expected to contribute to greater long-term improvements in utilization of oxygen in the brain, thereby leading to improvements in cognitive performance greater than those observed among patients who exercise but do not receive LVRS (Specific Aim 1). A health control group will be retested on similar neuropsychological tests in order to control for practice effects (Specific Aim 2). Although we do not expect significant differences in emotional (depression and anxiety)

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functioning across groups, this study will enable us to evaluate the relationship between emotional status and neuropsychological scores in the MT+ LVRS and MT groups following randomization. In addition, since major neurological events are more likely following surgery, and major neurological events affect cognitive function, we will evaluate the incidence of neurological events in our sample and will determine the degree to which neurological events are associated with cognitive function (Specific Aim 3). No studies have examined the relationship between change in cognition and improve quality of life in COPD patients following LVRS surgery, therefore, we aim to explore these associations in Specific Aim 4. We propose to compare changes following LVRS and MT by examining 84 NETT patients (42 in MT, 42 in LVRS) at three times points (baseline, post 6-10 week medical treatment MT, and 6 months post MT or LVRS randomization) using select neuropsychological, psychological, neurological and QoL tests. Forty normal controls will be tested at baseline and 6-10 weeks follow- up. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTINUOUS MEASUREMENT OF BREATHLESSNESS Principal Investigator & Institution: Baird, John C.; Psychological Applications, Llc 74 N Pinnacle Ridge Rd Waterbury, Vt 05676 Timing: Fiscal Year 2003; Project Start 10-SEP-2001; Project End 31-JAN-2005 Summary: (provided by applicant): The objective of this research is to evaluate a computer-assisted, continuous method for measuring breathlessness during exercise. The method represents a new approach to obtain subjective ratings from patients exercising on a cycle ergometer or treadmill. Whereas the "gold standard" Borg scale for measuring breathlessness is employed in over one million patients per year, it is limited by the fact that each estimate occurs at a discrete point in time cued or signaled by the health professional, rather than when the patient senses a change in symptom intensity. Moreover, if the patient cannot verbalize a response (e.g., while breathing through a mouthpiece), the rating must be indicated on the scale by finger pointing. During exercise this can lead to uncertainty on the part of the clinician as to exactly where the patient is pointing. The continuous method for obtaining patient-initiated ratings is unencumbered by these limitations, while also providing a direct measure of the absolute threshold and peak of breathlessness. The software to obtain such ratings has been shown to be reliable, valid, and easy to use. Thus far, the method has been successfully applied in patients with chronic obstructive pulmonary disease. The goal of Phase II is to evaluate the new methodology with a wider sample of adult patients afflicted with asthma, interstitial lung disease, respiratory muscle weakness, and pulmonary vascular disease, as well as with a group of children with asthma. Tests will also be conducted to investigate the responsiveness of the continuous method to track the effects of bronchodilator therapy and respiratory load. PROPOSED COMMERCIAL APPLICATION. The commercial goal is to replace the discrete scale with a computeradministered continuous method for measuring breathlessness during exercise. The product marketed in Phase III will be a computer software package that will be purchased by physicians, clinics and hospitals throughout the world. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COPD CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Lazarus, Stephen C.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008

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Summary: (provided by applicant): Investigators in the Division of Pulmonary and Critical Care Medicine at the University of California, San Francisco hereby apply to participate in a cooperative COPD Clinical Research Network, to examine existing and novel therapies and management strategies for COPD, and to rapidly disseminate the findings of this Network to the medical community. COPD is the 4th leading cause of death in the United States, and the associated financial and social burden is enormous. As new information on the pathobiology of COPD and new approaches for management appear, large, carefully conducted, collaborative multicenter studies are required to define the position of these new strategies in our therapeutic algorithm. Two specific protocols are included in this application; both test novel therapeutic approaches to important clinical problems associated with COPD. The first proposal, "The Effects of TNF-alpha Inhibition in COPD", examines the ability of a monoclonal antibody against the potent proinflammatory cytokine TNF-alpha to reduce the rate of exacerbations in patients with moderate-to-severe COPD. Exacerbations account for most of the emergency department visits, hospitalizations, and deaths associated with COPD. This proposal will examine the effect of anti-TNF-alpha therapy on exacerbations, and the relationship between exacerbations, symptoms, lung function, quality of life, markers of inflammation in airway secretions, and expression of epithelial cell genes related to mucus production. The second project, "Inhibition of Endothelin-1 in COPD-related Pulmonary Arterial Hypertension" will examine whether treatment with the Endothelin A and B receptor antagonist bosentan improves capacity in patients with pulmonary arterial hypertension, and the prognosis for these patients is poor. Evidence suggests that the pulmonary artery lesion is not due solely to hypoxemia, and that vasodilator therapy may be beneficial. This study will test an orally-administered therapy with bosentan, and clinically-important endpoints including exercise capacity, functional class, dyspnea, quality of life, and overall clinical status. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COPD CLINICAL RESEARCH NETWORK - DATA COORDINATING CENT* Principal Investigator & Institution: Connett, John E.; Professor; Biostatistics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The Division of Biostatistics in the School of Public Health at the University of Minnesota (John Connett, PI), in collaboration with the Divisions of Epidemiology and Pulmonary Medicine, proposes to establish and operate the Data Coordinating Center (DCC) for the Chronic Obstructive Pulmonary Disease Clinical Research Network. The goals of the Network are to identify preventive and therapeutic interventions to reduce mortality, exacerbations, and disability in patients with moderate-to-severe COPD. Clinical trials undertaken by the Network must have relevance to clinical practice for the treatment of this common and serious chronic disease, and must provide efficient answers to questions regarding treatment alternatives. As described in RFA HL-03-002, four-to-six clinical centers and the DCC will launch and complete 4-5 clinical trials in a 5-year period, with 2-3 protocols in operation simultaneously. As the DCC for the Network we will perform the following key functions: 1) establish the Network's organizational structure and facilitate internal communications; 2) provide statistical input on study design; 3) develop and maintain Manuals of Procedures; 4) establish a distributed data entry/data management system; 5) train and certify clinical center personnel; 6) create subcontracts with central laboratories and reading centers, as needed; 7) generate randomization schedules and

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reports to monitor data quality, recruitment progress, retention, outcomes, and adverse events; 8) carry out data analyses for the investigators and contribute to manuscripts and scientific presentations. Our group brings to this project over 16 years of experience in the design, conduct, and analysis of multicenter clinical trials of COPD and emphysema, including the Lung Health Studies I, II, and the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. We have assembled a solid and productive team of investigators and professional staff with relevant expertise in biostatistics, clinical trials, epidemiology, and pulmonary medicine, and ample experience in data management, data quality control, and statistical analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG THERAPY FOR PREVENTING COPD EXACERBATIONS Principal Investigator & Institution: Niewoehner, Dennis E.; Minnesota Veterans Reserach Inst 1 Veterans Dr Minneapolis, Mn 55417 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a rapidly growing global health problem and in the United States is now the fourth commonest cause of death. Symptomatic treatment for this disease is only modestly effective. Oxygen for hypoxemic patients and cigarette smoking cessation are the only known interventions that alter the natural history of the disease. Patients with established COPD frequently develop exacerbations, clinical episodes that are characterized by cough, sputum, and worsening dypsnea and caused mostly by infections. Exacerbations are very morbid and extraordinarily costly events that also accelerate deterioration in lung function. Hospitalization for COPD accounts for about two thirds of all health care expenditures for this disease. Antibiotics and systemic corticoteroids, common treatments for severe COPD exacerbations, are only marginally effective and their widespread use may be harmful to the patient and to society at large. Reducing the frequency of severe COPD exacerbations is very important, because even small reductions would confer large human and economic benefits. Described in this application is a proposal for two separate randomized clinical trials to determine whether low-dose theophylline or inhaled corticosteroids will reduce the frequency of severe COPD exacerbations. Once widely prescribed, theophylline has fallen into disfavor as a COPD treatment, partly due to safety issues. However, recent studies indicate that theophylline may prevent severe COPD exacerbations and that antiinflammatory activity is retained at lower and safer doses. Recent trials suggest that inhaled corticosteroids may also prevent severe COPD exacerbations, but these findings have yet to be fully confirmed. Each of the two proposed trials will randomize about 700 patients with moderate-to-severe COPD (FEV1 < 60% predicted) in equal numbers to active drug (low-dose theophylline or inhaled corticosteroids) or placebo for a one-year period. The primary outcome variable is the first occurrence of a severe COPD exacerbation (defined as an unscheduled clinic or urgent care visit requiring systemic corticosteroid therapy or hospitalization) or death from any cause. Secondary outcomes include spirometry, several measures of health care utilization, respiratory medication use, and safety. Both trials are designed with 80% power to show a 30% reduction in severe exacerbations at a significance level of 0.05. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFICACY OF YOGA FOR SELF-MANAGEMENT OF DYSPNEA IN COPD Principal Investigator & Institution: Carrieri-Kohlman, Virginia L.; Professor; Physiological Nursing; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Management of dyspnea (shortness of breath) is a major problem for patients with chronic obstructive lung diseases (COPD). The effectiveness of traditional supervised and home-based exercise programs for decreasing dyspnea is well established. The remaining knowledge gap is the efficacy of complementary exercises that patients report they are using to manage dyspnea, that may be more congruent with pulmonary patients' lifestyles and values, and that can be adapted to changes in illness severity and disability. Yoga practice is a complementary therapy that people use to manage their dyspnea. Previous studies lack controlled designs, large samples, protocol descriptions, or valid instruments for measuring dyspnea. The aims of this exploratory study are: 1) to develop a safe and feasible yoga program for patients with COPD; 2) to test the efficacy of this program, while establishing the decrease in dyspnea that may be expected with such a program; 3) to determine whether secondary outcomes of physical performance, psychological well being, and health related quality of life (HRQL) are positively affected by yoga practice; 4) to identify and contact community resources including physicians, nurses, yoga practitioners and facilities to support the testing of yoga training for patients with COPD in targeted communities. In a prospective randomized controlled trial three cohorts of subjects with moderate to severe COPD (N=36) will be randomly assigned to either an experimental yoga training or a usual care control for12 weeks. Outcomes will be measured at baseline, after each session, and immediately after the training program. If yoga is shown to affect dyspnea in patients with COPD, the findings of this exploratory study will serve as a foundation for the writing of a multi-center controlled trial to compare the effect of yoga training on dyspnea and multivariate outcomes to an attention control group and a usual care group with a larger sample of patients with moderate to severe COPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELECTROCHEMICAL OXYGEN CONCENTRATOR FOR HOME THERAPY Principal Investigator & Institution: Andrews, Craig C.; Lynntech, Inc. College Station, Tx 77840 Timing: Fiscal Year 2003; Project Start 01-MAY-2000; Project End 31-MAR-2005 Summary: (provided by applicant): The beneficial effects of Long-term Oxygen Therapy (LTOT) in the home for patients with Chronic Obstructive Pulmonary Disease (COPD), and other lung diseases causing hypoxemia, are well known. The number of patients with COPD is increasing in most countries, and in the U.S., it is now one of the leading causes of death. LTOT increases a patient's survival rate and also has the potential to improve considerably a patient's quality of life. Since LTOT must be given for as long as possible during the day, it is important to extend daily hours of oxygen therapy into the mobile period of the day. This can be achieved through the use of compact, lightweight, portable sources of oxygen gas. Thus, there exists a clear need for a new technologybased oxygen generator that satisfies all the requirements for LTOT both within and outside the home. Currently, providing ambulatory oxygen with LOX systems is

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problematic because of the cost of LOX and hence lower profit margins for suppliers. The aims of portable oxygen are to increase exercise tolerance, reduce exercise dyspnea, improve quality of life, and extend the daily hours of LTOT. In response to the identified need, this project is specifically aimed at improving the delivery of oxygen to ambulatory patients in the home and office setting using an innovative electrochemical life support system. The technology will have a dramatic improvement in clinical benefits, patient convenience and delivery costs. The portable electrochemical system will produce on demand a supply of humidified, but otherwise pure, oxygen gas, while having a system weight less than 10 Ib and system power requirements less than 600 Watts. The system will provide instantaneous start-up and it is estimated that the oxygen generator will cost less than $1,000. A dual-use development approach will be adopted because the portable electrochemical oxygen generator technology has both government and other commercial applications such as battlefield life support, forward medical treatment areas, casualty transport vehicles, "oxygen trickle charger" for commercial and military aircraft, and hyperbaric oxygen therapy for decompression sickness, air embolism, and carbon monoxide poisoning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENVIRONMENTAL AGENTS AS MODULATORS OF DISEASE PROCESSES Principal Investigator & Institution: Cory-Slechta, Deborah A.; Professor; Environmental Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-AUG-1980; Project End 31-MAR-2005 Summary: OVERALL (Taken from the Applicant's Description) Despite a marked increase in the human life span, questions about the role of environmental and occupational agents as modulators of disease and dysfunction continue to arise. These questions are provoked by such observations as the increased incidence of asthma in children, reports that Parkinson's disease (PD) has an environmental rather than a genetic basis, of correlations between ultra fine particles and cardiovascular respiratory morbidity and even mortality, and of endocrine-like chemical and reproductive dysfunction, among others. The goal of the University of Rochester NIEHS Environmental Health Sciences Center (EHSC) is to define the scope of the contribution of toxic agents to disease processes and dysfunctions and to understand the mechanisms by which they occur. The Center strives to provide a sound scientific basis for evaluating the health risks posed by chemical exposures to human populations and ultimately to prevent their occurrence. This is achieved through the efforts of four Research Cores. Studies within the Neurotoxicology Research Core seek to identify mechanisms by which toxicants affect nervous system function and thereby contribute to behavioral, neurological and psychiatric disturbances of the nervous system, such as Parkinson's disease, autism, and cognitive impairments. The Osteotoxicology Research Core focuses primarily on the extent to which lead exposure serves as a risk factor for disturbances of skeletal function, particularly its involvement in dental caries in osteoporosis. The Pulmonary Toxicology Research Core examines inflammatory and oxidative stress-induced mechanisms of lung injury and how disease states such as asthma, chronic obstructive pulmonary disease and others modulate these mechanisms. The Protein Modulators of Toxicity Research Core seeks to identify the ways in which toxicants modulate biologically active proteins critical to normal homeostatic function, thereby inducing changes contributing to disease processes. The scientific efforts of the Research Cores are promoted and assisted through five Facility/Service Cores: Transgenic Services, Pathology/Morphology/Imaging,

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Biostatistics, University Facilities and Shared Instrumentation. In addition, collaborations and new directions are significantly enhanced through the Enrichment Program of the EHSC, which includes a Pilot Project Program, a Visiting Scientist Program, the EHSC Seminar Series and the Rochester Conference Series. The Community Outreach and Education Program with its new Director, has instituted a Community Advisory Board that provides communication between the EHSC and the Community and has established educational programs for various segments of the community, including students and teachers, medical professionals and even senior scientists Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFICIENCY

ENVIRONMENTAL

FACTORS

IN

ALPHA

1-ANTITRYPSIN

Principal Investigator & Institution: Newman, Lee S.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2004 Summary: Occupational dust, fume, and gas exposures have been associated with the development of chronic obstructive pulmonary disease (COPD). Genetic and familial factors also contribute to the risk of COPD. Individuals with alpha1-antitrypsin deficiency (alpha11ATD) comprise one of these genetically susceptible populations. The major environmental risk factor for COPD and for alpha1AT deficient individuals who are homozygous (PI*Z) is personal tobacco use. However, preliminary studies suggest that occupational respiratory exposures may also contribute to the severity of this disease. We hypothesize that exposure to occupational and environmental respiratory irritants (dust, fumes, smoke, and gas) increases the risk of both chronic respiratory symptoms and airflow obstruction in genetically susceptible individuals with PI* Z alpha1AT deficiency. This hypothesis will be tested through the following specific aims: 1) To evaluate the association between specific types of occupational and environmental respiratory exposures and the presence and severity of specific pulmonary symptoms and airflow obstruction. 2) To assess the potential interaction or confounding effects between different types of respiratory irritant exposures and/or personal and environmental tobacco smoke in predicting risk of respiratory symptoms. 3) To assess the potential interaction between personal or environmental tobacco smoke and respiratory infections in predicting risk of respiratory symptoms and airflow limitation. 4) To validate the model developed as a predictive model by repeated re-sampling of the original data set, i.e. bootstrapping, that could help health professionals counsel and educate PI*Z patients concerning their risks from environmental and occupational exposures. A cross-sectional design will be used in an expanded cohort of >300 patients with alpha1At deficiency PI*Z. The goal of this proposal is to better understand the burden of obstructive lung disease due to occupational exposures in PI*Z individuals. Such research offers an opportunity to investigate environmental and genetic interactions in which the gene trait that confers susceptibility is known but in which the environmental triggers are not. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE AND DISABILITY IN COPD PATIENTS Principal Investigator & Institution: Berry, Michael J.; Health and Exercise Science; Wake Forest University 1834 Wake Forest Road Winston-Salem, Nc 27106 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-AUG-2006

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Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXHALED AIR BIOMARKERS IN COPD Principal Investigator & Institution: Voelkel, Norbert E.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): COPD is a world-wide health problem of increasing prevalence. Non-invasive markers of disease phenotype, severity and rate of progression of the disease, markers characterizing exacerbations of COPD are badly needed. We propose to analyze ultrafiltered exhaled air samples, to establish optimal protocols for sample collection following a FEV1 maneuver, to survey lipids including phospholipids, eicosanoids, steroids, nucleosides, proteins and peptides as markers of potential disease (activity). We propose to establish quantitative mass spectroscopic techniques (using stable isotope dilution protocols) for target marker assays. We propose to investigate stable COPD patients before and during supplemental continuous flow oxygen treatment, before and during alpha-l-antitrypsin infusion therapy, before and after smoking cessation and before and after lung transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FISH OIL INTAKE, BIOMARKERS AND CHANGE IN LUNG FUNCTION Principal Investigator & Institution: Barr, R Graham.; Medicine; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): We have recently observed a potentially protective effect of fish oil intake on the development of chronic obstructive pulmonary disease (COPD) using validated, questionnaire-based definitions of fish oil intake and COPD in the Nurses' Health Study. The primary aims of the current application are to replicate this promising finding with more precise measures of exposures and outcomes and to investigate potential molecular and genetic intermediaries in a population of 557 older, current and former smokers. The main hypotheses are: 1) dietary fish intake and n-3 PUFA levels are inversely associated with longitudinal lung function decline and CT lung density; 2) n-3 PUFA levels are inversely associated with biological intermediaries, such as leukotriene (LT)-B4, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and soluble adhesion molecules, and these intermediaries are on the causal pathway between n-3 PUFA levels and lung function decline; 3) related genes variants, such as those in genes coding for TNF-alpha, ICAM-1 and nitric oxide synthase (NOS) isoforms, identify individuals at higher risk of lung function decline. Baseline questionnaire, spirometry, and chest CT data and blood specimens have been collected for 557 participants, and one-year follow-up visits for questionnaire, spirometry and chest CT measures are currently ongoing. We propose to study the above hypotheses in this cohort of older, former and current smokers by extending follow-up for an additional four years; the total of six measures would yield adequate power to examine the important relationships between fish intake, n-3 polyunsaturated fatty acids (PUFA), inflammatory mediators, related gene variants and longitudinal lung function. Use of this existing cohort with previously collected blood samples will provide relatively costeffective results about this potentially promising and safe therapy for COPD.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL GENOMIC BIOMARKERS IN COPD Principal Investigator & Institution: Reilly, John J.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) affects over 18 million Americans. It is clear that the major environmental risk factor for this debilitating syndrome is cigarette smoking. It is not clear, however, what factors are responsible for the fact that some smokers develop the disease while most do not. Studies of potential therapies have been hampered by the lack of easily measurable characteristics that predict the course of the disease. Most studies have used measures of lung function as a marker of disease activity. Such studies typically require large numbers of patients and an observation period of months to years. This application proposes studies to develop alternative biomarkers associated with COPD. The research proposed will develop a set of candidate biomarkers by utilizing expression array profiling to characterize gene expression patterns in lung tissue and peripheral blood associated with the presence of COPD. These candidates will then be assessed in studies performed in populations previously characterized for COPD-related phenotypes: the Boston Early Onset COPD Study and the Normative Aging Study. The initial studies will involve expressionprofiling in both lung tissue and peripheral blood in samples obtained from patients undergoing pulmonary resections at Brigham and Women's Hospital. Samples from 20 patients with airflow obstruction on spirometry and emphysema demonstrated on chest CT scans will be compared to samples from 20 matched control patients. State of the art bioinformatic analytic techniques will be used to analyze these data and develop a list of candidate biomarkers based on expression differences. Polymorphisms in the candidate genes will then be studied for genetic association in two characterized populations with different disease distributions. The Boston Early Onset COPD Study consists of patients who have been diagnosed at an early age with severe COPD and their family members. In contrast, the Normative Aging Study includes participants with a broad spectrum of COPD. Studies in these populations will be directed at establishing whether differences in gene expression or gene polymorphisms are associated with COPD. It is hoped that these markers will provide insight into disease pathogenesis and serve as outcome assessment parameters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL GENOMICS CENTER FOR INNATE IMMUNITY PGA Principal Investigator & Institution: Vercelli, Donata; Professor; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local

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inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTONAL GENOMICS CENTER FOR INNATE IMMUNITY PGA Principal Investigator & Institution: Stampfer, Meir J.; Professor and Chair; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood

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diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS AND CONSEQUENCES OF NICOTINE ADDICTION Principal Investigator & Institution: Hoidal, John R.; Professor; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This is a revised application from faculty members at the University of Utah for support of a Program Project Grant (PPG) on the genetics and consequences of nicotine addiction. The broad objective of this PPG is to systematically dissect the genetic and molecular mechanisms of addiction and to determine the role of nicotine in the devastating clinical conditions caused by cigarette smoking, identifying specific facets that can ultimately be manipulated to prevent and/or effectively treat this devastating affliction. The thematic hypothesis being tested is that the susceptibility to both nicotine addiction and its consequences has underlying genetic components. In this hypothesis, nicotinic acetylcholine receptors (nAChRs) are critically involved in initiating the determining susceptibility to addiction and the consequences of cigarette smoking, including the dysregulated inflammation and abnormal repair that lead to chronic obstructive pulmonary disease (COPD). The hypothesis will be addressed by combining studies of candidate gene and linkage analysis using the powerful Utah family database and a well-established COPD database with studies using mouse genetics and biology. The studies are designed to generate new knowledge that will improve our understanding of the genetics of addiction and its consequences. In the PPG, productive established investigators with excellent track records of interaction have combined to direct three projects and four cores. Each project addresses novel mechanisms and is oriented around the central theme. Each project is supported by new preliminary data that document the importance and feasibility of the proposed studies. We believe that the proposal offers the special advantages of established research programs, proven multidisciplinary collaborative interactions and a rich environment for productive basic and clinical

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research. By orienting the proposal around the genetics of addiction and its consequences, all three projects interact and intrinsically reinforce each other in almost every phase of their studies. The "intellectual structure" of the PPG is as follows: Project 1, combines the use of unique patient populations with "state of the art" techniques for genotyping and large scale nucleotide sequencing to investigate the genetics of nicotine addiction in humans. Project 2 complements the studies of Project I by delineating the genetic mechanisms that contribute to the formation and maintenance of tolerance to nicotine through nAChRs using well-characterized inbred mice and gene-targeting approaches. Project 3 uses the genetic approaches employed in Project I and animal models developed in the inbred mouse strains used in Project 2 to explore the role of nicotine in the pathogenesis of COPD and the genetic basis for COPD. An Administrative Core, an Animal Core, a Microarray Core and a Resequencing and Genomic Analysis Core support the three projects. The revised proposal has been restructured in response to the initial review and is much stronger. It offers established research programs coming together in multi-disciplinary collaborative interactions for productive basic and clinical research on an important societal problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENOTYPING CENTER FOR INNATE IMMUNITY PGA Principal Investigator & Institution: Kwiatkowski, David J.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify

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SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: H. INFLUENZAE MODULINS IN COPD AIRWAY INFLAMMATION Principal Investigator & Institution: Clemans, Daniel L.; Biology; Eastern Michigan University Ypsilanti, Mi 48197 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2005 Summary: (provided by applicant): Non-typeable Haemophilus influenzae (NTHi) is the most common bacterial cause of exacerbations of chronic obstructive pulmonary disease (COPD). These exacerbations are characterized by a brisk inflammatory response with the accumulation of polymorphonuclear leukocytes (PMN) in the lungs of patients with COPD. Essential to this inflammatory response is the expression and secretion of proinflammatory cytokines by host respiratory cells in response to NTHi. The mechanisms, by which NTHi stimulate a proinflammatory response by host respiratory cells and the progressive airway destruction in COPD, is unclear. Therefore, the overlying hypothesis of the proposed research is that secreted, nonlipooligosaccharide (LOS), NTHi proteins (i.e., modulins) stimulate the production of proinflammatory cytokines from human respiratory cells contributing to the endobronchial inflammation in COPD. The long-term goal of this project is to define the mechanisms by which specific secreted NTHi modulin(s) affect the recruitment and activation of effector cells in NTHi endobronchial infection. This goal will be met through identifying, purifying, and characterizing one such secreted modulin and its corresponding gene from model H. influenzae strain Rd and analyzing the modulin's role in respiratory inflammation in vitro. We will study the following Specific Aims to address the hypothesis. Specific Aim I will identify the secreted modulin from H. influenzae that stimulates a proinflammatory response in respiratory epithelial cells by 1) isolating the secreted modulin from H. influenzae strain Rd; 2) analyzing the secreted modulin gene from H. influenzae strain Rd; and 3) reconstituting the H. influenzae strain Rd modulin activity using the purified modulin. Specific Aim II will assess the distribution and expression of the secreted modulin gene from clinical isolates of NTHi. These studies will provide important insights into the mechanisms of the host inflammatory response in NTHi endobronchial infection of COPD and potentially identify novel therapeutic strategies to be employed in the treatment of this debilitating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HE3 MR DIFFUSION & LOW DOSE CT QUANTITATION OF EMPHYSEMA Principal Investigator & Institution: Gierada, David S.; Radiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-JUL-2006

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Summary: (provided by applicant): The goal of this proposal is to develop and evaluate hyperpolarized helium-3 diffusion magnetic resonance imaging (He-3 dMRI) and low dose quantitative computed tomography (LD-QCT) indexes of emphysema as noninvasive biomarkers for the presence, severity, and progression of emphysema. Emphysema is a pathologic abnormality of the lungs defined by enlargement of terminal airspaces and destruction of airspace walls, and is commonly present in the millions of patients with chronic obstructive pulmonary disease. Increased knowledge regarding the role of inflammatory mechanisms and proteinases in the pathogenesis of COPD is leading to searches for newer anti-inflammatory strategies and enzyme inhibitors. Though in the early stages of development, some of these new approaches may eventually provide therapy that alters the course of the disease. Accurate biomarkers of emphysema would allow for early diagnosis, intervention, and evaluation of new therapies. Though spirometry is used to diagnose COPD, it is a relatively inaccurate means of assessing for emphysema. Conventional CT is a highly accurate way to assess the severity of emphysema, which can be quantified by the decrease in xray attenuation of the lungs that results from airspace enlargement and alveolar destruction. However, CT is performed using relatively high doses of ionizing radiation, which limits its acceptability as a screening and follow-up test, particularly in early or mild disease. In recent years, other noninvasive imaging tests for emphysema have been designed that require no or greatly reduced ionizing radiation. One new test, He-3 dMRI, uses a specially constructed MRI pulse sequence to measure the degree to which diffusivity of inhaled hyperpolarized He-3 gas is restricted by alveolar walls. This measurement, the apparent diffusion coefficient (ADC), is increased (gas diffusion is less restricted) when alveolar spaces are enlarged in emphysema. Another test, low dose CT scanning, allows depiction of substantial lung detail at less than 20 percent of the radiation dose of conventional CT, but has not been developed for quantitation of emphysema. Though promising, the optimal technique and validity of both He-3 dMRI and LD-QCT have yet to be established. We hypothesize that 1) Optimizing He-3 dMRI and LD-QCT techniques will allow sensitive and accurate assessment of emphysema, compared to lung morphometry, 2) The optimized He-3 dMRI and LD-QCT techniques will provide valid biomarkers of emphysema that can be applied to other populations, and 3) He-3 dMRI and LD-QCT will allow identification of emphysema progression over time. We will study three separate groups of subjects. In the first group, we will determine which scanning and analysis parameters provide ADC and LD-QCT biomarkers that most accurately quantify the amount of emphysema present pathologically in lobectomy specimens (Aim I). We will then use the optimized scanning and analysis techniques to validate these measurements in a different group, compared to the amount of emphysema present in lobectomy specimens (Aim II). In a third group of subjects, we will determine ADC and LD-QCT lung attenuation measurements at serial time points to assess for emphysema progression (Aim III). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEALTH EFFECTS OF AIR POLLUTION IN AN ELDERLY POPULATION Principal Investigator & Institution: Sullivan, Jeffrey H.; Environmental and Occupational Health Studies; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 05-AUG-2002; Project End 31-MAY-2007 Summary: (provided by applicant) The long term goal of the candidate is to develop a patient oriented research program in Pulmonary Medicine and Environmental Health at

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the University of Washington that determines mechanisms of pulmonary and cardiovascular effect from environmental pollutants. The candidate will perform two studies to determine the effects of PM2.5 on cardiac function. The first study is a casecrossover study which will determine the association of sudden cardiac arrest to PM2.5 and co-pollutant levels. The second is a panel study in elderly individuals that will expand on the understanding of mechanism of cardiac effect by determining whether inflammatory cytokine and thrombotic responses to particulate matter (PM), CO or N02 occur in susceptible sub-populations. It hypothesizes that these air pollutants induce an inflammatory cascade within the lung that results in measurable elevations in local and systemic inflammatory mediators that induce a decompensation of cardiac function, especially in susceptible groups. These proposed studies of inflammatory markers will be coupled to measures of intra-individual changes in thrombotic proteins (D-dimer and fibrinogen) with varying levels of air pollution exposure in this cohort of elderly participants with and without lung and heart disease. The proposed study builds on an established project within the UW EPA PM Research Center repeatedly measuring personal PM exposures and health effects, in 108 elderly individuals with and without cardiac or respiratory diseases during a high and low pollution season. By assessing intra-individual differences, this project will: 1) Determine whether PM exposure-effect relationships can be detected for exhaled nitric oxide and for serum TNF-alpha and TNF-alpha receptors, IL-6 and IL-6 receptor, endothelin-1 and C-reactive protein (CRP) and whether these effects are associated with sub-clinical morbidity including a reduction in heart rate variability. 2) Determine whether elevated PM 2.5 is associated with increased susceptibility to thrombosis by measuring intra-individual variation of D-dimer and fibrinogen levels. Elucidating molecular mechanisms of susceptibility to air pollution induced morbidity will aid in designing public health policy to prevent morbidity and mortality from air pollution. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEART ATTACKS AND TRAFFIC POLLUTION Principal Investigator & Institution: Schwartz, Joel D.; Director of Research & Development; Environmental Health; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant ): Since the late 1980's, numerous studies have found particulate air pollutant concentrations to be responsible for excess mortality. More recent studies have clarified that most of these deaths are sudden deaths. We have recently shown that particles from traffic are more specifically associated with acute cardiovascular effects. We have also shown the pre-existing diabetes was an important modifier of the particle effect. All of these studies have looked at immediate effects. Two prospective cohort studies have indicated that long-term exposure to particles is also associated with noticeable reductions in life expectancies. To replicate the association between chronic exposure and deaths, and examine the specific role of traffic particles we will conduct a case-control study of myocardial infarctions, using data from the Worcester Heart Attack Study. We will use a GIS system to code the latitude and longitude of home and work locations of cases and controls, and fit models relating concentrations of elemental carbon (a tracer for traffic particles) to population density, distance from roadways, and traffic counts in the Worcester MSA. From this, we will assign exposures to each subject. Controls will be sampled from town census books, which are conducted annually in Massachusetts. Controls will be matched by age, sex, and 10 year age group. Socio-economic data will be merged from the block group of the

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subjects, and questionnaire data will assess smoking history, alcohol consumption, aspirin and other medication use, educational level, height, weight, age, race, exercise, and air conditioner use. We will also ask about the presence of medical conditions, such as diabetes, that may be modifiers of the effect of pollution. Nonlinearities in covariates will be assessed and controlled for using penalized splines, in conditional logistic regressions. A preliminary analysis will use retrospective data, and not obtain questionnaire data. Effect modification by diabetes, prior MI, COPD, smoking, and angina will be tested using interaction terms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOW ACCESS AFFECTS OUTCOMES OF REHABILITATION SERVICES Principal Investigator & Institution: Iezzoni, Lisa L.; Associate Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2005 Summary: (provided by applicant): With the aging population, the number of Americans with functional limitations will rise by over 300% by 2049 if the age-specific prevalence of major chronic conditions remains unchanged. While medical interventions can sometimes dramatically improve physical functioning, restoring functional abilities is unrealistic for many people. The focus shifts to preserving function, slowing its decline; and preventing secondary complications. Rehabilitation services, including physical therapy (PT) and occupational therapy (OT), are central to these efforts. Few studies have examined the outcomes of PT and OT as they are routinely practiced throughout communities in the United States. This project will use a longitudinal, nationwide survey of Medicare beneficiaries over and under age 65 (the 1994-2001 Medicare Current Beneficiary Surveys), linked with respondents' Medicare claims, to examine outcomes of PT and OT. A major change in Medicare payment policy -- the 1997 Balanced Budget Act, which tightened payments for rehabilitation services -- will serve as a "natural experiment" of conditions under which access to routine rehabilitation care is constrained. The proposed study aims to examine the association between the intensity of PT and OT services and likelihood of good outcomes, including lower rates of: self-reported functional decline; worsening overall health; activities of daily living (ADL) and instrumental ADL dependence; institutionalization; acute care hospitalization; injury prompting medical attention; decubitus ulcer development; purchase of assistive technology; social isolation; and death. The study will examine persons within five conditions: arthritis; stroke; acute myocardial infarction; chronic obstructive pulmonary disease; and lower extremity mobility problems, regardless of cause. Two inter-related hypotheses will guide this work: (1) increased intensity of PT and OT is associated with better outcomes; and (2) decreased access to PT and OT is associated with worse outcomes. These hypotheses will be tested using cross-sectional and longitudinal analyses; analytic techniques will include time series, propensity score, instrumental variable, and proportional hazards regression modeling. The primary outcome of the proposed study will be an assessment of the association of PT and OT, as routinely practiced nationwide and important outcomes of care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHALED PARTICLE CHARACTERISTICS AND EARLY LUNG EFFECTS Principal Investigator & Institution: Beckett, William S.; Professor; Environmental Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627

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Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: (Adapted from the Investigator's Abstract) Chronic obstructive pulmonary disease (COPD) is a disabling condition produced by chronic bronchitis (airway inflammation and mucus hypersecretion) and emphysema (loss of alveolar surface area). Epidemiologic studies of the workplace have consistently shown an excess of COPD associated with dusty work environments, yet only a few substances (coal, silica, cadmium) causing COPD in the workplace have been characterized based on chemical composition and respirable particle size. These findings suggest that the much broader range of workplace dusts may in certain conditions contribute to COPD based on characteristics other than chemical composition alone. Pulmonary inflammation plays a role in early events leading to COPD. Particles less than 10 micron aerodynamic diameter are considered to be able to penetrate the upper airways and reach the respiratory tract, and are thus designated as being in the respirable range. Ambient fine particles (

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