Huntington's Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

HUNTINGTON’S 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 ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Huntington’s 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: 0-597-83933-6 1. Huntington’s 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 Huntington’s 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 HUNTINGTON’S DISEASE.......................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Huntington’s Disease ................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 62 CHAPTER 2. NUTRITION AND HUNTINGTON’S DISEASE .............................................................. 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Huntington’s Disease ................................................................ 109 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 118 CHAPTER 3. ALTERNATIVE MEDICINE AND HUNTINGTON’S DISEASE ....................................... 119 Overview.................................................................................................................................... 119 National Center for Complementary and Alternative Medicine................................................ 119 Additional Web Resources ......................................................................................................... 127 General References ..................................................................................................................... 127 CHAPTER 4. DISSERTATIONS ON HUNTINGTON’S DISEASE ......................................................... 129 Overview.................................................................................................................................... 129 Dissertations on Huntington’s Disease ..................................................................................... 129 Keeping Current ........................................................................................................................ 130 CHAPTER 5. CLINICAL TRIALS AND HUNTINGTON’S DISEASE .................................................... 131 Overview.................................................................................................................................... 131 Recent Trials on Huntington’s Disease ..................................................................................... 131 Keeping Current on Clinical Trials ........................................................................................... 133 CHAPTER 6. BOOKS ON HUNTINGTON’S DISEASE ........................................................................ 135 Overview.................................................................................................................................... 135 Book Summaries: Online Booksellers......................................................................................... 135 The National Library of Medicine Book Index ........................................................................... 136 Chapters on Huntington’s Disease ............................................................................................ 137 CHAPTER 7. MULTIMEDIA ON HUNTINGTON’S DISEASE ............................................................. 139 Overview.................................................................................................................................... 139 Bibliography: Multimedia on Huntington’s Disease................................................................. 139 CHAPTER 8. PERIODICALS AND NEWS ON HUNTINGTON’S DISEASE .......................................... 141 Overview.................................................................................................................................... 141 News Services and Press Releases.............................................................................................. 141 Academic Periodicals covering Huntington’s Disease............................................................... 145 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 147 Overview.................................................................................................................................... 147 U.S. Pharmacopeia..................................................................................................................... 147 Commercial Databases ............................................................................................................... 149 Researching Orphan Drugs ....................................................................................................... 149 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 153 Overview.................................................................................................................................... 153 NIH Guidelines.......................................................................................................................... 153 NIH Databases........................................................................................................................... 155 Other Commercial Databases..................................................................................................... 157 APPENDIX B. PATIENT RESOURCES ............................................................................................... 159 Overview.................................................................................................................................... 159 Patient Guideline Sources.......................................................................................................... 159 Associations and Huntington’s Disease .................................................................................... 163

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Finding Associations.................................................................................................................. 164 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 167 Overview.................................................................................................................................... 167 Preparation................................................................................................................................. 167 Finding a Local Medical Library................................................................................................ 167 Medical Libraries in the U.S. and Canada ................................................................................. 167 ONLINE GLOSSARIES................................................................................................................ 173 Online Dictionary Directories ................................................................................................... 175 HUNTINGTON’S DISEASE DICTIONARY ........................................................................... 177 INDEX .............................................................................................................................................. 233

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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 Huntington’s 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 Huntington’s 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 Huntington’s 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 Huntington’s 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 Huntington’s 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 Huntington’s 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 HUNTINGTON’S DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Huntington’s 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 Huntington’s 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 “Huntington’s 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: •

Dysphagia Caused by Neurologic Deficits Source: Otolaryngologic Clinics of North America. 31(3): 507-524. June 1998. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Summary: Normal swallowing is a complex, dynamic neuromuscular activity that depends on a set of physiologic behaviors resulting in liquid and solid material moving efficiently and safely from the mouth to the stomach. Problems with swallowing in the oropharynx (oropharyngeal dysphagia) are often linked to neurologic or muscular diseases. This article reviews the neurologic lesions and conditions that account for the majority of oropharyngeal dysphagia cases. The authors first review the physiology and

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neurophysiology of both normal and abnormal swallowing, then outline the recommended patient physical examination and laboratory work up. Each neurological disease that may contribute to oropharyngeal dysphagia is then discussed: amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, myasthenia gravis, stroke (cerebrovascular accident), and laryngeal nerve injury. Dysphagia secondary to acute neurologic deficits, along with other abnormalities, tends to improve with time. Dysphagia resulting from chronic neurologic conditions, however, often worsens as the disease process evolves. 4 tables. 62 references. •

Severity of Cognitive Impairment in Juvenile and Late-Onset Huntington Disease Source: Archives of Neurology. 55: 835-843. June 1998. Summary: This journal article describes a study of the severity of cognitive impairment and the influence of motor and cognitive deficits on functional disability across different ages of onset of Huntington's disease (HD). The participants were 71 patients seen at the HD program in the Departments of Neurology and Genetics at the Fundacion Jimenez Diaz in Madrid, Spain. The patients were divided into three groups based on onset of motor symptoms: juvenile onset (at age 25 years or younger, n=15), adult onset (at age 26 to 50 years, n=43), and late onset (at age 51 years or older, n=13). Healthy controls, matched on age and education to groups 1 and 3, also were studied. All patients were assessed with a battery of neuropsychological tests, measures of motor and functional abilities, and a genetic analysis to determine the number of CAG trinucleotide repeats. Patients with juvenile onset had the longest CAG repeat lengths and those with late onset had the shortest. Cognitive impairment was less severe in the juvenile-onset group than at other ages of onset. Visuospatial function was more impaired in patients with late onset, and prefrontal functions were more impaired in those with juvenile onset. Functional disability was associated with global cognitive status in patients with late onset, and with motor deficits and prefrontal dysfunction in those with early onset. 3 figures, 5 tables, 54 references.

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Electrophysiological Analysis of Altered Cognitive Functions in Huntington Disease Source: Archives of Neurology. 54: 1089-1098. September 1997. Summary: This journal article describes an electrophysiological analysis of altered cognitive functions in Huntington's disease (HD) in the domains of visual processing and memory. Nine patients with HD and 9 controls matched for age, sex, and education participated. Cognitive event-related potentials (ERPs) were measured, using an electroencephalogram, under three conditions: a parallel visual search task, a serial visual search task, and a word-recognition memory task. The components of averaged ERPs were quantified by latency and amplitude measures, and analyzed along with behavioral measures (search time, hit rate, and recognition accuracy). The results suggest that compared with controls, the patients with HD showed a significant delay in the early visual components and abnormalities in the ERP indexes of word recognition and target detection. These changes were accompanied by a marked delay in search times and a greatly reduced accuracy on the memory task. The ERPs on the memory task were different from those found in studies of patients with Alzheimer's disease, suggesting a different neural basis for the deficits in HD. 6 figures, 4 tables, 77 references.

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Inherited Neurodegenerative Diseases and Transgenic Models Source: Brain Pathology. 6(4): 467-480. 1996.

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Summary: This journal describes the clinical features, neuropathological changes, and genetics of several neurodegenerative diseases, outlines transgenic strategies for creating animal models, and reviews investigations in which these approaches have been used to model several genetic neurodegenerative diseases. The discussion focuses on the familial forms of Alzheimer's disease (FAD) and amyotrophic lateral sclerosis (FALS), and the spectrum of triplet-repeat disorders. Researchers have linked some cases of FAD to mutations in genes encoding the amyloid precursor protein or presenilin 1 or 2. Some cases of FALS have been linked to mutations in the superoxide dismutase 1 gene. Spinocerebellar ataxia and Huntington's disease are associated with trinucleotide repeat expansions in the genes encoding ataxin 1 and huntington, respectively. Recently, investigators have used transgenic mouse models of these disorders to examine the mechanisms by which the expression of mutant proteins causes autosomal dominant disease. Their collective experience suggests that the expression of high levels of mutant transgenes in nervous tissue can significantly increase the chance that the transgenic mice will develop phenotypes resembling those occurring in autosomal dominant human diseases. The emerging view is that each of these diseases results from the gain of a toxic property by the mutant protein. Future research will be aimed at understanding the biological basis of these toxic properties and, ultimately, to the development of new treatments for the neurodegenerative disorders. 220 references. •

Apolipoprotein E Alleles as Risk Factors in Alzheimer's Disease Source: Annual Review of Medicine. 47: 387-400. 1996. Summary: This review article discusses apolipoprotein E (apoE) alleles as risk factors in Alzheimer's disease (AD). Three early-onset forms of AD inherited as autosomal dominant traits account for less than 2 percent of prevalent AD. A major susceptibility locus, apoE, is associated with risk and age of onset distributions for the common familial and sporadic late-onset AD. The identification of additional genetic susceptibility genes in the etiology of AD and the metabolic mechanisms leading to differences in age of onset and disease pathogenesis are active areas of current research. The operational difference between using apoE genotyping in differential diagnosis from the application of autosomal dominant traits, such as the triplet repeat size of the Huntington gene in Huntington's disease, is that the absence of the disease-associated marker does not rule out the disease. 1 table, 2 figures, 66 references. (AA- M).

Federally Funded Research on Huntington’s Disease The U.S. Government supports a variety of research studies relating to Huntington’s 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.

2 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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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 Huntington’s 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 Huntington’s disease. The following is typical of the type of information found when searching the CRISP database for Huntington’s disease: •

Project Title: 2001 CAG TRIPLET REPEAT DISORDERS Principal Investigator & Institution: Brundin, Patrick; Gordon Research Conferences Box 984, 512 Liberty Ln West Kingston, Ri 02892 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: This application is to request funding for the 2001 Gordon Research Conference on CAG triplet repeat disorders to be held in Mount Holyoke College, MA, USA, July 15-20, 2001. Two major groups of genetic neurological disorders were recently identified as unstable triplet repeat diseases. Their discovery represents the foundation of a new set of principles in genetics. One group of diseases includes fragile X, myotonic dystrophy and Friedreich's ataxia. Patients with these disorders all exhibit an expansion of triplet repeats in a non-coding sequence of the DNA genome. In the contrast, the other group of neurologic disorders exhibit expanded triplet repeats (coding for CAG bases) in the coding part of the genome, resulting in a polyglutamine tract. This latter group includes Huntington's disease, spino-cerebellar ataxia 1, 2, 3, 6 and 7, spinobulbar muscular atrophy and dentato-rubral pallido-luysian atrophy. These disorders results in a selective loss of neurons in the brain and spinal cord, with a different anatomical distribution in each disease. Although the genetic defects are established, it remains to be elucidated how the mutant gene in each case generates the specific pathogenetic process and how this leads to a characteristic anatomical pattern of changes. The identification of these mutant genes raises hopes for many affected by severe genetic disease. However, before development of novel therapies can be expected, it is necessary to better understand the disease processes. This requires a multi-disciplinary research effort with collaborative projects between scientists from diverse specialties ranging from fruit fly genetics to clinical neurology and neuropathology. This conference on CAG triplet repeat disorders will gather both young and senior, key scientists who will present provoking lectures on the cuttingedge of science. In keeping with the Gordon Research Conference format, there will be generous time allocated to both structured discussions led by peers and for informal discussions and social generous time allocated to both structured discussions led by peers and for informal discussions and social interaction. Strong emphasis is placed on training and mentoring of young scientists and time is also devoted to career issues. All participants (except speakers and discussants) will be encouraged to present posters. When participants are selected there will also be priority given to women, minorities, and persons with disabilities Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A NEW METHOD OF DRUG DISCOVERY FOR CNS DISEASES Principal Investigator & Institution: Lowe, David; Envivo Pharmaceuticals, Inc. 3696 Haven Ave, Ste B Redwood City, Ca 94063 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-DEC-2003

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Summary: (provided by applicant): The discovery and development of small molecule therapeutics for disorders of the Central Nervous System (CNS), particularly for neurodegenerative diseases, is one of the major challenges of modern biomedical research. Although great advances have been made in understanding the biological basis of neurological disorders, this scientific progress has not yet been translated into effective new treatments for these devastating disorders. This application proposes to exploit recently developed disease models in the fruit fly Drosophila melanogaster to develop a new and innovative method of small molecule drug discovery that is articularly well suited for CNS diseases. We propose to use automated procedures to screen well-validated disease models of two trinucleotide repeat disorders, Huntington's disease and spinocerebellar ataxia type I, for compounds that improve motor function. In Phase I of this project, we will use an automated screening system to develop and validate disease-specific assays, and establish by proof-of-principle experiments that the system can provide high-throughput assays that are rapid, reproducible, and highly sensitive to improved motor function in the two disease models. In Phase II, we will use this system to carry out a moderately large-scale screen (12,000 compounds) against both disorders and will begin a characterization of the "hits" that we obtain in both Drosophila and mouse disease models. The proposed project has two important outcomes. The first is to validate a method of drug discovery by in vivo screening of disease models that can be used not only for further screening for these two diseases, but also as a more general method for neurological and behavioral disorders. The second is the discovery of new bioactive compounds that can ameliorate these diseases in Drosophila, and are thus suitable lead candidates for further preclinical and clinical development in mammals, and ultimately in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVATION OF STRESS RESPONSE IN NEURODEGENERATION Principal Investigator & Institution: Sagara, Yutaka; Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: (Applicant s abstract) The deleterious effects of age-related neurodegenerative diseases are not only felt at the personal level but also as an everincreasing financial burden on the national healthcare system. However, there is no cure or a preventive treatment currently available for neurodegenerative diseases such as Alzheimer's disease (AD). Elucidation of the mechanisms underlying selective neuronal death observed in AD may help conceptualize a new treatment or a therapeutic approach. Oxidative stress, though a culprit of neuronal death observed in AD and other neurodegenerative diseases, may also activate a survival response by regulating a subset of proteins and genes, resulting in selective protection of neurons. Characterization of such a survival response, therefore, is an important step toward prevention of neuronal death as well as promotion of neuronal survival. The central hypothesis of this proposal is that the activation of the signal transduction cascade involving phosphatidylinositol 3-OH kinases (PI3K) confers resistance to oxidative injury caused by amyloid beta (ABI-42), while the down regulation of this pathway by chronic exposure to AB results in neurodegeneration. In this context, the main objectives of this project is to define the role of PI3K cascade in neurodegeneration observed in AD by investigating the effects of AB on PI3K in a comprehensive multi-system which includes human brains with AD, APP transgenic mice, and neuronal cell cultures. During the course of the proposal, the applicant will receive additional training in clinical aspects of neuroscience such as neuropathology in the context of AD

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neurodegeneration. Also, with the aid of the sponsor and consultants, the applicant will obtain training in the transgenic mouse models, which can be used to test the above hypothesis as well as to develop therapies for treatment of age-related neurological disorders. Finally, the award will assist the applicant to become an independent faculty member actively involved in research in age-related neuro-degeneration as well as in teaching at a biomedical research institution such as UCSD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVITY-DEPENDENT REGULATION OF SYNAPSES BY SHANK Principal Investigator & Institution: Hung, Albert Y.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to investigate the role of a newly discovered postsynaptic protein, Shank, in the regulation of dendritic spine morphology and cytoskeleton. Local electrical stimulation induces growth of dendritic spines, suggesting that synaptic activity directly modulates neuronal architecture and circuitry. The molecular basis for these activitydependent changes is not known, but probably involves postsynaptic proteins that interact with receptors and/or cytoskeletal elements. Shank acts as a putative scaffold for multiple glutamate receptor subtypes and also binds to the actinbinding protein cortactin, which has been implicated in dynamic cytoskeletal rearrangement and translocates to synapses in response to glutamate. This study examines the role of Shank in the regulation of dendritic spines and its in vivo function through three specific aims. First a combination of cell biological, biochemical, and dominant inhibitory approaches will be used to determine the mechanism for glutamateregulated cortactin translocation to synapses, and to identify if Shankcortactin interaction is required for this response. Second, how Shank induces spine growth will be studied by structurefunction analysis. Finally, a genetic approach, generation of a Shank1 "knockout" mouse, will be used to investigate the role of Shank proteins in brain development, in postsynaptic receptor organization, and in learning and memory. The longterm goal of the candidate is to understand how aberrant synaptic transmission contributes to neurologic disease. Synapses are the signal processing units of the brain, and overexcitation of synapses by glutamate is thought to play a role in both acute neuronal injury (such as stroke and seizure) and chronic neurodegenerative conditions (including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis). Understanding how postsynaptic proteins, such as Shank, regulate activitydependent synaptic plasticity may shed light on mechanisms of glutamate toxicity. The immediate goal is to obtain training in the most uptodate techniques in molecular genetics, protein biochemistry, and cellular neurobiology, sponsored by Dr. Morgan Sheng, which will enable him to become a productive, independent molecular neurologist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALYSIS OF TORSIN PROTEIN FUNCTION IN C. ELEGANS Principal Investigator & Institution: Caldwell, Guy A.; Biological Sciences; University of Alabama in Tuscaloosa Tuscaloosa, Al 35487 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Dystonia is estimated to be six times more prevalent than Huntington's Disease, ALS, or Muscular Dystrophy. However, as few as 5% of the over 350,000 persons in North America estimated to be affected have been correctly

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diagnosed and are under treatment (NIH Budget Office). The most severe early-onset form of this disorder has been linked to a mutation in a human gene named TOR1A that encodes torsinA, a protein that is also localized to inclusions in the brains of Parkinson's patients termed Lewy bodies. While a causative genetic mutation has been identified, the cellular mechanisms of pathogenesis underlying dystonia remain unknown. We are applying the advantages of the model organism, Caenorhabditis elegans, towards a detailed analysis of two specific torsin-related gene products in this nematode. The chromosomal positioning of these genes suggests that they may represent a functionally co-expressed unit and preliminary studies from our laboratory indicate they act neuronally. Phylogenetic analysis of the torsin family indicates these proteins share distant sequence similarity with the functionally diverse AAA+ family of proteins. We have determined that ectopic overexpression of a C. elegans torsin homolog results in a reduction of polyglutamine repeat-induced protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression quantitatively persisted as animals aged. Antibody staining of transgenic animals using antisera specific to TOR-2 indicated this protein was highly localized to sites of protein aggregation. We propose to extend these preliminary studies through a combination of reverse genetic approaches designed to investigate the cellular role of torsin proteins in the nematode. The specific aims of the proposed project include: 1) to determine what phenotypes are associated with C. elegans torsin homologues; 2) to define sites of C. elegans torsin protein function; and 3) to determine potential effectors of torsin activity. These studies will further our understanding of the molecular mechanisms responsible for early-onset torsion dystonia. Moreover, the aberrant protein deposition associated with diverse neurodegenerative disorders like Parkinson's Disease and those caused by polyglutamine expansion such as Huntington's Disease warrants further investigation of any putative neuroprotective effects of torsins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOMATED BRAIN PARCELLATION AND MORPHOMETRY Principal Investigator & Institution: Halgren, Eric; President; Cortechs Labs, Inc. Charlestown, Ma 02129 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-DEC-2002 Summary: Non-invasive visualization of the living human brain with MRI (magnetic resonance imaging) is an essential part of clinical neurology. Until now, evaluation of structural changes in diseases have mainly relied upon qualitative visual judgements, or tedious hand labeling. This project aims to develop MRI image processing software that will automatically segment the entire brain volume into its constituent tissues and structures. This segmentation allows quantification of tissue volumes and intrinsic parameters. The software will be interoperable with our suite of structural and functional MRI software tools, allowing, for example, subcortical regions of interest to be examined for functional activation. We propose to base the tissue segmentation of intrinsic properties of brain tissue, thus rendering it independent of pulse sequence or scanner manufacturer. This will greatly increase scan/rescan reliability which is crucial for multi-site clinical trials, or for within-subject repeated measures (e.g., comparing tumors or multiple sclerosis plaques over time). The proposed software will allow MRI data to be used to detect neuropsychiatric disease monitor the course of such diseases, and evaluate the effectiveness of treatments. Research and clinical applications can be expected in several neurodegenerative and psychiatric diseases such as schizophrenia, Alzheimer's and Huntington's disease. PROPOSED COMMERCIAL APPLICATIONS:

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Huntington’s Disease

The proposed product would be of interest to researchers and clinicians using MRI, i.e., >10000 scanners worldwide. The proposed software could become a standard part of many brain MRI scans, in order to detect and quantify pathology, and thus could potentially be used in a substantial proportion of the millions of brain scans performed every year. Initially, the software would be used to perform surrogate markers of CNS effectiveness in drug evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL ASSESSMENT OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Bazzett, Terence J.; Psychology; College at Geneseo 1 College Cir Geneseo, Ny 14454 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2005 Summary: (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disease that manifests initially as motor and cognitive dysfunction followed by a relentlessly chronic progression of symptoms culminating in death. The cause of HD is a genetic aberration on the short arm of the 4th chromosome identified as an expansion of a CAG trinucleotide repeat. Molecular biologists have very recently begun developing genetically altered mice, designed to mimic the expanded CAG repeat in HD. Technology advances have created a unique situation whereby development of new lines of mice has outpaced careful behavioral analysis of phenotypes. As a result, numerous models have been created without a clear understanding of how genetic differences affect phenotype differences. Perhaps more importantly, there is currently no consensus on what features of these models best mimic features of the disease they represent. Lacking a clear understanding of behavioral deficits vastly reduces the usefulness of any genetic model designed to mimic a disease that manifests with profound behavioral symptoms. The current proposal is a series of experiments designed to undertake detailed assessment of motor abnormalities and some cognitive dysfunction in mouse models of HD. In particular abnormalities in coordinated limb movements will be assessed beginning at a relatively early age. The first aim is to conduct experiments in a model currently known to express other gross behavioral abnormalities later in development. Once methods for assessing early subtle motor/cognitive deficits are established, the second aim is to assess genetically more appropriate models that reportedly express few gross behavioral abnormalities. The long-term objective will be initiated in the third aim where potentially therapeutic drugs will be assessed. Drug therapies that attenuate early/subtle deficits in mice may be useful in treating HD. Such therapeutic potential may not be recognized using current methods that assess only major dysfunction expressed late in development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BEOWULF LINUX CLUSTER COMPUTER Principal Investigator & Institution: Destefano, Anita L.; Neurology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2004 Summary: (provided by applicant): A major goal of the human genome initiative is to access genetic information to understand and to prevent and/or treat human disease. The recently completed "draft" sequencing of the human genome and the recent advances in biotechnology that allow rapid throughput of samples for genotyping have created a vast resource of information. However, the challenge to dissect the genetic and

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environmental factors influencing susceptibility for common diseases remains statistically complex and computationally intensive. The genetic epidemiologists and statistical geneticists at the Boston University Medical Campus have a long history of success in identifying genes associated with risk for both simple Mendelian diseases as well as complex traits. In order to continue this success and to implement the most recent advances in statistical genetics, we are requesting, a Beowulf class LINUX cluster of 192 Intel processors. This computing system will be dedicated to genetic analysis including linkage analyses and association testing. The system will support the research of 14 NIH funded projects. Although the phenotypes and study populations differ widely among the funded projects of the major users, there is substantial overlap in the computationally intensive genetic analysis techniques that will be performed on this system. This cluster will enable computation of identity by decent relationships in extended pedigrees, computation of empirical p-values via simulation, and application of complex gene by gene and gene by environment interaction models. There is strong institutional support for this system evidenced by the administration's commitment to funding a full time systems administrator and long term support of upgrades and maintenance The placement of this computing resource among the investigators of this proposal will have a broad impact in the field of genetics and further our understanding of the genetics of Huntington's Disease, Alzheimer's Disease, Obesity, Stroke and Hemostatic Factors, Cognitive Decline, Hypertension, Cardiovascular traits, and Cocaine and Opioid Dependency among others. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOENERGETICS IN ANIMAL MODELS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Beal, M Flint.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 15-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): The pathogenesis of Huntington's Disease (HD) is as yet unknown but there is substantial evidence that both altered gene transcription as well as mitochondrial dysfunction play an important role. There is evidence that huntingtin binds to transcription factors which results in decreased expression of genes which may play a critical role in neuronal survival. A secondary consequence of this appears to be impaired oxidative phosphorylation and increased generation of reactive oxygen species. In our prior grant, we showed that there was impaired oxidative phosphorylation in transgenic mouse models of Huntington's disease, and that this was associated with increased oxidative damage. We also showed that agents such as creatine and coenzyme Q, which improve cellular bioenergetics, exert neuroprotective effects in transgenic mouse models of Huntington's disease. In the present proposal, we intend to extend these studies to two further unique transgenic mouse models of Huntington's disease. We will determine whether there is mitochondrial dysfunction and oxidative damage in a knock-in mouse model developed by MacDonald and colleagues. These mice are a very accurate genetic model of Huntington's disease. We will also examine the tetracycline-off model developed by Yamamoto and colleagues to determine whether there is mitochondrial dysfunction and oxidative damage with the gene turned on, which then resolves once the gone is turned off. We will carry out similar studies with an inducible cell culture model. We will investigate whether histone deacetylase (HDAC) inhibitors exert neuroprotective effects by altering gene transcription in transgenic mouse models of Huntington's disease. We will examine whether a phosphodiesterase IV inhibitor can exert neuroprotective effects in transgenic

12

Huntington’s Disease

mouse models of HD by increasing cyclic AMP levels, leading to increased CREB transcriptional activity, and whether this improves mitochondrial function. Our prior studies showed that combinations of agents, which target different disease mechanisms in Huntington's disease, may exert additive neuroprotective effects. We will, therefore, examine whether a combination of creatine or coenzyme Q with either a HDAC inhibitor or a phosphodiesterase IV inhibitor can exert additive neuroprotective effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELL GROWTH AND DIFFERENTIATION IN THE VERTEBRATE EMBRYO Principal Investigator & Institution: Lacy, Elizabeth H.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2001 Summary: (Adapted from the Investigator's Abstract): Gastrulation is a fundamental developmental process, and in the mouse it coordinates complex cell and tissue movements with cell growth and proliferation to reorganize and differentiate the embryonic ectoderm into the definitive ectoderm, mesoderm, and endoderm germ layers of the fetus. The genetic pathways directing gastrulation are only beginning to be unraveled by both targeted and random mutagenesis in the mouse and fish. Intriguingly, a number of gastrulation stage mouse mutants have been discovered through the targeted disruption of genes that are known, through their involvement with human disease, to participate in the basic cellular processes of proliferation, differentiation, and signal transduction. Recent examples include the fibroblast growth factor receptor (Fgfr-1), Brca1, Brca2, Huntington's disease homologue (Hdh), and the tumor suppressor Smad4/Dpc4. Thus the study of novel gastrulation stage mouse mutants is likely to lead to the identification of genes that serve pivotal functions in the coordination of cell growth, proliferation, and differentiation. The subject of this proposal is amnionless (amn), a recessive transgene insertional mutation that disrupts the assembly of the middle streak, this portion of the primitive streak that gives rise to non-axial embryonic mesoderm, such as somitic mesoderm. This novel phenotype reveals that the formation of the middle streak is mediated by a previously unknown pathway, one that is genetically separable from those directing the formation and specification of the proximal and distal streak regions. Therefore, a disrupted gene at the amn locus must play a key role in this pathway. Chimera analyses have shown that this gene, the amn gene, functions in the visceral endoderm to direct the formation of the middle streak and thus, that amn defines a new role for the visceral endoderm during gastrulation. The primary objective of this proposal is to positionally clone the amn gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR PATHOGENIC MECHANISMS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Tobin, Allan J.; Professor and Director; Brain Research Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 25-JAN-2001; Project End 31-DEC-2004 Summary: Huntington's disease is a devastating neurodegenerative disease that is inherited as an autosomal dominant. Disease-causing alleles encode expanded polyglutamine tracts in the aminoterminal region of huntingtin (htt), a large protein

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whose normal function is unknown. The unifying hypothesis in this proposal is that htt containing an expanded polyglutamine tract (htt-ex) causes proteasome poisoning by irreversibly blocking proteasomes. We argue that poisoned proteasomes in postmitotic neurons results in a failure of normal protein turnover and in cell dysfunction and death. Wild-type htt (htt-wt should not produce such effect. The proposed studies will consider not only the poisoned- proteasome hypothesis but also alternative hypotheses, in which the pathogenic action of htt-ex does not depend on proteasomes. We have organized these studies around three Specific Aims: 1. To determine whether the intracellular distribution and the pathogenic effects of htt-ex expression vary with cell type and proliferative state. 2. To examine the effect of htt-ex expression on proteasome function and on the turnover of specific proteins, including htt itself. 3. To examine the effects of htt-ex expression on neuronal function and to determine whether known proteasome inhibitors can mimic these effects. At the conclusion of these three sets of proposed experiments we will know 1) whether proteasome location and function change in response to cell cycle and htt expression; (2) whether htt affects proteasome function and protein turnover either directly or indirectly; (3) whether htt-ex alters cellular function in dividing and stationary, differentiated cells; and (4) whether proteasome inhibitors mimic htt-ex-induced changes in neuronal function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CENTER FOR GENE-ENVIRONMENT STUDIES IN PARKINSON DISEASE Principal Investigator & Institution: Chesselet, Marie-Francoise S.; Charles H. Markham Professor of Neurolog; Brain Research Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 26-AUG-2002; Project End 31-JUL-2007 Summary: The Center for Gene-Environment studies in Parkinson disease at UCLA (UCLA-CGEP) will bridge three major NIH and VA-supported awards in Parkinson's disease (PD) and one NIH-sponsored study of Huntington's disease. The central hypothesis of the proposed UCLA-CGEP is that gene and environmental toxins combine to increase the risk for PD in susceptible individuals through an interplay between pesticides and mechanisms regulating dopamine homeostasis. We postulate that critical factors in this interaction are oxidative stress and resulting alterations in proteasomal function. Project I "Environmental toxins and genes that influence dopamine in Drosophila and humans" will examine interindividual variability of dopamine vesicular transporter (VMAT) expression due to promoter variants in two human populations in parallel with a reporter gene assay. These populations will be genotyped for functional VMAT2 variants and association analyses of gene-environment interactions and pesticide exposures collected in the parent grant will be conducted. In addition, Drosophila genetics will be used to determine how the expression of VMAT affects dopamine-mediated toxicity and identify genes that modulate VMAT function, which will then be examined in the human population for their relevance to increased risk of PD. Project II "Interaction between pesticides and genetic alterations in dopamine homeostasis in mice" will test the hypothesis that pesticides and genetic variations in combination increase the vulnerability of dopaminergic neurons, and that one of the mechanisms involved is oxidative stress. Genetically engineered mice with a reduction in expression of VMAT or the cytoplasmic dopamine transporters, and mice with altered expression of alpha-synuclein and parkin, two proteins known to cause familial PD, will be examined. Behavior and quantitative anatomy will be used to assess the effect of pesticides on dopaminergic neurons in these genetically altered mice.

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Huntington’s Disease

Histology, gene expression profiling, in vivo neurochemistry and slice electrophysiology will be used to examine the role of oxidative stress in this interaction. Project III, "Pesticides and Proteasomal Dysfunction: genetic susceptibility in cellular models" will test the hypothesis that proteasomal dysfunction is central to the deleterious effects of the combined environmental and genetic insults. Cell lines, primary neuronal cultures from genetically altered mice, and human lymphoblasts will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CEREBRAL NEURODEGENERATION

MITOCHONDRIAL

METABOLISM

IN

Principal Investigator & Institution: Powers, William J.; Associate Professor; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: (Adapted from the abstract provided by the applicant): Several lines of evidence suggest that Huntington's disease (HD) and Parkinson's disease (PD) have defects in mitochondrial function that impair oxidative phosphorylation and play a key role in the mechanism of neuronal death. To date, however, there have been no direct measurements of cerebral oxygen to glucose metabolic ratios to demonstrate an in vivo defect in cerebral mitochondrial metabolism in these diseases. We will use positron emission tomography (PET) to measure in vivo regional cerebral oxygen metabolism (CMR02) and cerebral glucose metabolism (CMRglc) to test two primary hypotheses: 1) Patients with HD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 gene-positive pre-symptomatic patients with HD, 15 gene-positive patients with HD and definite motor signs and 30 age/gender-matched normal controls. 2) Patients with PD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 never-medicated, early PD patients and 15 age/gender-matched normal controls. In the same subjects, we also will test two secondary hypotheses: 3) Regions vulnerable to pathologic insult have larger magnitude or selective defects in cerebral mitochodrial metabolism - caudate and putamen in HD and substantia nigra and putamen in PD. 4) In PD and HD, the degree of dysfunction in platelet electron transport complex function measured in vitro correlates with the degree of abnormal cerebral mitochondrial metabolism measured in vivo. At this time it is not clear how the abnormalities in electron transport chain activity measured in vitro in these two diseases correspond to cerebral mitochondrial metabolism in vivo. Direct in vivo regional PET measurements of CMR02 and CMRglc will allow us to demonstrate the extent and magnitude of mitochondrial dysfunction in vivo. Establishing the existence of cerebral mitochondrial dysfunction early in the course of these diseases will not only provide insights into the pathogenesis, but it will provide a measurable biological abnormality that can be monitored to determine the effect of treatments aimed at slowing or halting the progression of neuronal loss. The opportunity to determine the relation between platelet mitochondrial function and cerebral mitochondrial metabolism in patients with PD and HD is uniquely important. If such a relationship can be established in untreated patients in this study, then we would pursue further studies to determine the effects on cerebral mitochondrial metabolism of agents that alter platelet mitochondrial function. If such studies yield consistent results, they will establish the basis for the utilization of platelet rnitochondrial function assays to monitor cerebral mitochondrial metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS Principal Investigator & Institution: Nowick, James S.; Professor; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 01-APR-1994; Project End 31-MAR-2003 Summary: beta-Sheet interactions between proteins play a critical role in many biological processes associated with diseases and with normal function. Examples including the binding of Ras and Rap by the serine/threonine kinase Raf in cell signaling and oncogene expression, the dimerization of HIV protease, and the interaction between the CD4 receptor and the HIV viral protein gp120. beta-Sheet formation is also involved in the aggregation of peptides and proteins to form insoluble beta-sheet structures that are associated with a variety of devastating neurological disorders, including Alzheimer's disease, Creutzfeld-Jacob disease and other prion diseases, and Huntington's disease. This proposal seeks to mimic and to disrupt betasheet interactions by using chemical model systems called "artificial beta-sheets." The broad, long-term objectives of this research encompass both the development of drugs for diseases involving beta-sheet formation between proteins (e.g., cancer, Huntington's disease, and Alzheimer's disease) and the development for general strategies for creating compounds that disrupt beta-sheet interactions. The specific aims are as follows: (1) Artificial beta-sheet structures based upon the beta-sheet at the interface of the two halves of the met repressor dimer will be synthesized dimer will be synthesized, and their structures will be studied by NMR and CD spectroscopy. (2) An artificial betasheet designed to mimic the protein G binding region of the Fab portion of the immunoglobulin G will be synthesized, and its interaction with domain III of protein G will be studied by NMR spectroscopy. (3) An artificial beta sheet designed to mimic the beta-sheet interface between Ras proteins and the c-Rafl kinase (Raf) and artificial betasheets that mimic the binding regions of Ras and Raf will be synthesized. Their structures and interactions will be studied by CD and NMR spectroscopy, and the latter two compounds will be evaluated for anti-cancer activity by the NCI using an in vitro 60 human tumor cell line screen. (4) Artificial beta-sheets designed to mimic polyglutamine beta-sheet aggregates, which are involved in Huntington's disease and other genetic neurodegenerative diseases will be synthesized. Their structures will be studied by CD and NMR spectroscopy, and their ability to block polyglutamine beta-sheet aggregation will be determined using an in vitro assay. (5) Artificial beta-sheets designed to block beta-amyloid aggregation will be synthesized, and their abilities to block its aggregation and deposition will be studied using in vitro assays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHROMATIN REMODELING IN TRANSGENIC MOUSE MODELS OF HD Principal Investigator & Institution: Cha, Jang-Ho J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Huntington's disease is an autosomal dominant neurodegenerative disease for which there is currently no effective treatment. Although a number of pathogenic mechanisms have been proposed, transcriptional dysregulation has emerged as a potential critical aspect. In transgenic mouse models of HD, numerous alterations in the steady state levels of mRNA have been described. However, the mechanisms underlying mRNA perturbation are undefined. Elucidation of such mechanisms will have significant relevance to the understanding and development of future treatment of

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HD. In eukaryotes, gene expression is regulated through modification of chromatin and association with specific transcription factors. While alteration of steady state mRNA levels in transgenic HD mouse (R6/2) brain is de facto evidence of transcriptional dysregulation, it is yet unknown whether there are specific alterations in chromatin structure. In this project, we will explore chromatin remodeling in a transgenic HD mouse model. First, we will determine if mithramycin--an aureolic antibiotic that binds to GC-rich regions of DNA and which has been shown to extend lifespan in R6/2 mice-corrects mRNA expression abnormalities that we have previously described in these mice. We will use receptor binding autoradiography and in situ hybridization to perform these analyses. Next, we will seek to determine the role of a fatnily of transcription factors, the Sp family, with a set of genes whose expression is known to be altered in R6/2 mice. We will explore the interactions of Sp and related zinc finger transcription factors by using Chromatin ImmunoPrecipitation (CHIP) assays with realtime PCR detection. Finally, we will explore the ability of mithramycin to reverse chromatin abnormalities in the R6/2 mice. Taken together, these experiments will elucidate the molecular mechanisms underlying transcriptional dysregulation in a model of Huntington's disease. Such elucidation of a central pathogenic mechanism will open the way towards rational, mechanism-targeted therapy for this devastating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASES

COMPARATIVE

MODELING

OF

NEURODEGENERATIVE

Principal Investigator & Institution: Link, Christopher D.; Inst of Behavioral Genetics; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Numerous age-associated neurodegenerative diseases [e.g., Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), etc.] are associated with aggregation of disease-specific proteins. The finding that the genes encoding these proteins are mutated in some familial forms of these diseases strongly argues that these aggregating proteins cause these diseases. However, for all these diseases the relationship between protein aggregation and cellular pathology has not been clearly established. It is also unknown if the common association of protein aggregation with these diseases reflects a common underlying toxic mechanism, or, alternatively, a common downstream result of cell pathology. We will seek to identify the molecular consequences resulting from the aggregation of three different disease-associated proteins by individually expressing these proteins in a transgenic Caenorhabditis elegans model system. These molecular consequences will be determined by DNA microarray-based gene expression studies and co-immunoprecipitation analyses. Comparison of the molecular responses to expression of different disease-associated proteins will allow identification of common and disease-specific responses. We will then use the molecular genetic tools available in C. elegans to manipulate these molecular responses to determine their role in disease protein toxicity. These studies will directly test whether there is a common underlying toxic mechanism for these neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPUTATIONAL ANALYSIS OF HUMAN 'AT-RISK' DNA MOTIFS Principal Investigator & Institution: Stenger, Judith E.; Assistant Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Taken from the Candidate's Abstract) At-Risk DNA Motifs (ARMS), which include repetitive elements such as Alu sequences, homonucleotide runs and triplet repeats, are potentially unstable segments of the human genome. ARMS are a factor in genetic susceptibility to disease, requiring particular combinations of genetic backgrounds and environmental triggers to express a disease phenotype. While some of the mechanisms are understood, it is not clear under what circumstances repetitive DNA elements mediate pathological mutagenesis. Although a high burden of these sequences is generally tolerated in humans, they can have an enormous impact on health by contributing to diseases that have devastating effects on afflicted individuals. For example, Alus have been linked to numerous diseases including Fanconi anemia, alphazerothalassemia, leukemia, hypertension, neurofibromatosis, breast, and colon cancers. Trinucleotide repeat expansions have been linked with Kennedy's Disease, Huntington's Disease, myotonic muscular dystrophy, and Friedreich ataxia. The long term objective of this proposal is to gain insight into the genetic factors that mitigate gene rearrangement in hopes of predicting when the presence of a repetitive element truly constitutes a threat to the health of an individual. The hypothesis is that the characterization of ARMS according to all possible attributes (i.e. size of repeats, separation distances between repeats, orientation, sequence similarity between repeats, nucleotide base constitution and proximity and/or containment of mutagenic and/or toxicological agent targets, DNA processive or other enzymatic target sites) can reveal largely excluded situations that can be viewed as unstable. It is also postulated that a multidimensional database of repetitive sequences characterized according to the aforementioned attributes can be used to predict repetitive elements that are most prone to mutation, ARMS, while increasing our understanding of the interactions between these genetic elements and their environment. The approach is to use a combination of computational biology and molecular genomic analysis to locate and analyze ARMS. The specific aims of this proposal are to: 1) characterize available data according to the conceivable relevant attributes of size, distance, orientation, degree of homology, base constitution and containment of known target sequences. 2) To test the hypothesis by computationally identifying loci that have already known to contain ARMS linked to a mutation resulting in disease, and then to identify specific genes that may be at-risk for mutation and experimentally testing them using molecular biological approaches. 3) To set up an interactive on-line database and program server so that the scientific community can use the information and apply it to drive experimental research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--GENE EXPRESSION PROFILING Principal Investigator & Institution: Luthi-Carter, Ruth; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Extensive genome sequencing efforts and advances in microarray technology have converged to create revolutionary new opportunities for high-throughput analyses of gene expression. Within the context of the Program, gene expression analyses will provide information critical to elucidating the mechanisms by which huntingtin and

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Huntington’s Disease

DNA-binding therapeutic agents alter gene expression. The Gene Expression Profiling Core will support the Program's individual Projects by tracking the expression of thousands of mRNAs simultaneously in the respective experimental systems, thereby identifying the specific gene targets of a given pathological or pharmacologic manipulation. Identifying the gene promoters subject to a particular effect will allow the promoter elements and transcription factor(s) responsible for the change to be elucidated. The Gene Expression Core will provide expertise in the design, execution and analysis of microarray profiling studies and will carry out confirmatory analyses using independent methodologies, such as northern blotting. The Principal Investigator of the Core has extensive experience in microarray based expression analyses, including several previous studies of mouse models of polyglutamine disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Nehl, Carissa R.; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The proposed study will examine depression in presymptomatic Huntington's disease (HD). Presymptomatic individuals will be recruited through the NIH-funded PREDICT-HD study. This training proposal consists of two distinct stages. During the first stage, data collected during the PREDICT-HD study will be analyzed. The relationship between reported depression symptom severity, approximate nearness to disease onset, verbal memory, working memory, and visuospatial ability will be assessed. Additional information will be collected during the second stage of this proposal: a subgroup of individuals participating in PREDICT-HD will be assessed for mood disorders using the SCID and will complete a measure of relationship distress. This study will assess the relationship between mood disorders, nearness to disease onset, relationship distress, working, memory, and visuospatial ability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOES CORTEX KILL STRIATUM IN HD? Principal Investigator & Institution: Meade, Christopher A.; Anatomy and Neurobiology; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): An important question in Huntington's disease (HD) pathogenesis is whether mutant huntingtin (Ht) effects striatal cell death directly by perturbing striatal cell fL motion or whether it alters areas outside the striatum (notably cortex) that influence the striatum, leading indirectly to striatal cell death. This could be studied by examining the effect of a 100% mutant cortex on a 100% wild-type (VVT) striatum, and vice versa. We propose to develop a novel model system, creating in oculo co-transplants of mixed genotypic pairings, using embryonic HD mutant mouse and WT tissue, of cortex and striatum. Our studies will develop the in oculo method to test the competing hypotheses: 1) that a cortical action of mutant Ht drives striatal injury, even in the absence of the HD mutation in striatum, 2) that striatal injury can occur in a mutant striatum, even in the presence of an input from a WT cortex or in the absence of any cortical input or 3) that striatal injury is driven by a combination of a cortical and striatal action of mutant Ht. In Aim 1 we will create in oculo co-transplants

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using embryonic HD mutant cortical tissue and embryonic WT striatal tissue and look for signs of striatal cell injury as compared to co-transplants of WT cortex and WT striatum. If the hypothesis is correct, WT striatum wilt show increased signs of injury when co-transplanted with a HD mutant cortex. In Aim 2 we will create in oculo co transplants using embryonic WT cortical tissue and embryonic HD mutant striatal tissue and look for signs of striatal injury as compared to WT controls. If striatal injury depends on cortical input, but not mutant input per se, a HD mutant striatum will show signs of injury when co-transplanted with a WT cortex. Additionally, we will create single transplants of embryonic mutant striatum and look for signs of striatal injury. If striatal cell death is entirely cell autonomous, even in the absence of cortical input, striatal injury will occur in a HD mutant striatum, in Aim 3 we will create co-transplants using embryonic HD mutant cortex and embryonic HD mutant striatum and look for signs of striatal injury as compared to controls. This hypothesis predicts that striatal injury will only occur when an HD mutant cortex is co-transplanted with an HD mutant striatum or that it will be more severe than if only cortex or striatum is mutant. These studies will validate the in oculo technique as an effective HD model system, which might be useful in further testing hypotheses of mutant Ht mechanism of action and in testing possible drug therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOPAMINERGIC MODULATION OF WORKING MEMORY IN PD Principal Investigator & Institution: Hershey, Tamara G.; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): The applicant is a clinical neuropsychologist with graduate training in neuropsychology and postdoctoral training in neuropharmacology and positron emission tomography (PET). The goal of this career development award is to integrate and advance these two areas of interest to answer questions about the neuropharmacological and neurophysiological basis of cognitive dysfunction in movement disorders such as Parkinson's disease (PD). This award will provide the applicant with training in the technical and theoretical issues related to using cognitive and pharmacological activation techniques in functional magnetic resonance imaging (fMRI). Long-term objectives are to address questions about the neural basis of cognitive dysfunction in movement disorders related to dopaminergic and/or basal ganglia dysfunction, such as PD, Tourette's syndrome and Huntington's disease. In addition, questions about the effects of dopaminergic treatments for these and other disorders (e.g. dystonia) on cognitive and neurophysiological functioning are also of interest. Cognitive dysfunction in these diseases, either due to the disease process itself or its treatments, can be limiting and disabling. Understanding the neurophysiologic basis for these symptoms may aid in assessing the effectiveness of current treatments or in developing better treatments. During the award period, the applicant will develop expertise in the use of fMRI, cognitive and neuropharmacological techniques to study these disorders, and will continue to hone her clinical skills in the neuropsychological assessment of movement disorders. The applicant will apply these new techniques to investigate the role of dopamine in working memory. The specific aims of the proposed studies are to test the hypothesis that 1) PD affects prefrontal cortex involvement in working memory and 2) dopaminergic modulation of working memory primarily occurs due to changes in lateral prefrontal cortical activity. To test these hypotheses, the applicant will first perform a behavioral study examining the effects of a steady-state infusion of levodopa, a dopamine precursor, on verbal and spatial working memory in

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PD patients and controls. The results of this study will then guide the choices of working memory tasks for an fMRl study. Subjects will be asked to perform working memory tasks before and during a steady-state infusion of levodopa. Modulation of the lateral prefrontal cortex is predicted during levodopa infusion. The degree of modulation is predicted to depend on baseline dopaminergic status (PD vs control) and the degree of memory load (low vs high). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EDUCATING PHYSICIANS ABOUT GENETICS AND BRAIN DISORDERS Principal Investigator & Institution: Tanner, T Bradley.; President; Clinical Tools, Inc. 431 W Franklin St, #30 Chapel Hill, Nc 27516 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 31-MAR-2002 Summary: The expanding field of molecular genetics has quickly outpaced the knowledge of medical providers, due in part to the Human Genome Project. The genetics of brain illnesses are only beginning to be understood, nevertheless, providers treating patients with mental health, substance abuse and neurological disorders need to understand clearly what is and is not known about genetics and brain illnesses. It is likely that genetic aspects of schizophrenia, autism, mental retardation, bipolar disorder, among others, will be further identified in the near future, creating confusion and difficult choices for patients and families. Current and future providers must be prepared to explain and understand genetic susceptibility as it applies to a full range of illnesses. In Phase I, we will develop and evaluate an Internet-based CE program focusing on genetic issues related to alcoholism. We will also use the course the discuss upcoming technologies as well as issues related to discussing genetic risk with a patient. Phase II will produce 7 additional course on a variety of topic related to illnesses of the brain including Mixed Substance Abuse, Alzheimer's Disease, Schizophrenia, Affective Disorders, Attention Deficit, Huntington's Disease, and Mental Retardation. For each course we will highlight: 1) how genetic knowledge may affect patients and be used in clinical practice; 2) communication of genetic knowledge with patients and families: preparing for patients' questions; 3) where relevant, ethical, legal and psychosocial issues related to genetic testing, and 4) understanding emerging technologies and findings in genetics. A multidisciplinary team including representatives from psychiatry, genetics, genetic counseling, and primary care will create the content. We will evaluate the courses' effect on knowledge, clinical skills and self-efficacy using simple randomized studies comparing subjects using the genetics course to subjects using an online CE course on another topic. If successful, the training will expand the capabilities of the existing pool of providers and improve the training of future providers regarding the role of genetics in illnesses of the brain. PROPOSED COMMERCIAL APPLICATIONS: Physicians are required to obtain CME credit to maintain licensure and privileges. Managed care organizations (MCOs), such as large HMOs, may be interested in purchasing access to CE that can be offered to participant professionals. Pharmaceutical companies may also want to support development of courses based on the model described in this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EMBRYONIC STEM CELL MODEL OF POLYGLUTAMINE DISEASE Principal Investigator & Institution: Lorincz, Matthew T.; Neurology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274

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Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Huntington's disease (HD) is one of nine fatal neurodegenerative disorders without effective treatment or cure, caused by an expanded CAG/polyglutamine repeat. The roles of the normal and mutant HD gene product, huntingtin remain uncertain. The objective of the proposed Mentored Clinical Scientist Development Award is to explore huntingtin mediated neurodegeneration. We propose to evaluate the roles of transcriptional dysregulation and protein processing in HD by pursuing the following Specific Aims: Specific Aim 1: Define the role of the NMDA receptor subunit NR2B, CBP, histone acetylation, and BDNF in aberrant neurite outgrowth and decreased survival of embryonic stem (ES) cells with expanded CAG repeats. Specific Aim 2: Identify transcripts involved in expanded polyglutaminemediated transcriptional dysregulation. Specific Aim 3: Characterize the processing of polyglutamine containing proteins in undifferentiated and neuronally differentiated ES cells. We will pursue these Specific Aims utilizing an accurate, easily accessible, murine ES cell model. We find that neuronally differentiated ES cells with expanded CAG repeat domains develop features consistent with polyglutamine-mediated toxicity. Proposed experiments are expected to characterize full-length huntingtin protein processing and identify if the NMDA receptor subunit NR2B, CBP, histone acetylation, or BDNF are mediating neuronal dysfunction that precedes neurodegeneration in HD. Comparison of transcriptional profiles from neuronally differentiated ES cells with and without CAG repeats will be utilized to identify novel factors involved in HD pathogenesis. Once the pathologic mechanisms of mutant huntingtin are understood it will become possible to design rational therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPRESSION PROFILING FROM MICRODISSECTED SAMPLES Principal Investigator & Institution: Goldrick, Marianna M.; Senior Scientist; Ambion, Inc. 2130 Woodward St, #200 Austin, Tx 78746 Timing: Fiscal Year 2003; Project Start 01-FEB-2001; Project End 31-MAR-2005 Summary: (provided by applicant): One objective of the proposal is to develop a product line that will consist of amplified RNA (aRNA) derived from pure populations of cells from various regions of mouse brain. The target cells will be selected by Laser Capture Micro-dissection (LCM). The product line will include aRNA derived from normal mice and from mutant mice that serve as models of human neurodegenative disorders, including Alzheimer's disease, Huntington's disease, and ataxia telangiectasia. The product will be targeted to researchers carrying out expression profiling studies that aim to understand the molecular basis of normal neurological function and the molecular pathology of neurological disease. During the first year, efforts will be focused on scaling up procedures for sample processing, micro-dissection, and RNA isolation and amplification from normal mice. During the second year the procedures will be applied to the mutant strains. The aRNA will be produced using T7mediated in vitro transcription. In order to help meet the anticipated Production-scale goals, efforts will be directed to adapting the procedures, especially RNA amplification, to a robotic platform. In order to assess the RNA from micro-dissected samples for quality assurance purposes, molecular markers will be identified to use for verifying that the RNA is derived from the intended cell population. Efforts will also be directed to improving methods for identifying target cells for micro-dissection in samples such as tumors, where target cells (e.g. malignant cells) cannot always be distinguished by histological staining. The methods will be compatible with isolation of intact RNA from the selected cells, so that it can be amplified for use in microarray expression profiling

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assays. To meet this goal we will develop rapid fluorescent detection methods using primary fluorescent antibodies directed to tumor antigens, and we will also adapt detection of target cells in transgenic animals expressing Green Fluorescent Protein for use with LCM. Achieving these goals will provide aRNA from distinct cellular subtypes to neuroscience researchers who do not currently have access to this resource. Use of aRNA from defined cell subtypes, as opposed to bulk tissue, will improve the ability to make biologically meaningful conclusions from expression profiling experiments carried out on highly heterogeneous tissues such as brain. Another goal of the project is to release a kit for recovery of high-quality total RNA from microdissected samples, especially those obtained by LCM. The kit will be of general use to life science researchers working with micro-scale samples. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXTRAPYRAMIDAL SYSTEMS Principal Investigator & Institution: Graybiel, Ann M.; Professor; Brain and Cognitive Sciences; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2001; Project Start 01-JUL-1988; Project End 31-MAY-2002 Summary: (Investigator's Abstract): Dysfunctions of the basal ganglia have been implicated in extrapyramidal movement disorders such as Parkinson's disease and Huntington's disease, and the basal ganglia are abnormal in some neuropsyctuatric disorders as well. No clear idea has yet emerged, however, about what neural operations are performed in the basal ganglia. Strong evidence suggests that the functions of the basal ganglia must depend heavily on their cortical inputs, because the neocortex provides most of the inputs that the basal ganglia receive. These inputs enter mainly by way of corticostriatal projections to the striatum, and indirectly via the thalamus. The largest outputs of the basal ganglia in turn link these nuclei, through series of synaptic steps, to the motor, promotor and prefrontal cortex. The basal ganglia thus appear. to receive cortical input, process it under the influence of modulatory inputs (for example dopaminergic) and return it to the frontal lobes (and to some brainstem sites). We propose a coordinated series of experiments in monkeys and rats to study cortical-based ganglia linkages. Specifically, we propose to analyze in detail the sensorimotor cortical projections to the striatum. This sensorimotor system has significant advantages for study: the inputs are strong, they can be identified electrophysiologically by recording and microstimulation in the cortex, they can be mapped rigorously with sensitive tracer methods, and they thus can be analyzed in depth to permit stud of the map-transformations that occur between cortex and striatum. Much of the proposed work on this system (AIMS 1,2 and 4) is to be in squirrel monkey, in which we and others have found a distributed, catchy organization of inputs from primary somatosensory and motor cortex to the putamen. We will attempt to determine the rules of organization of these distributed and modular sensorimotor inputs. A series of studies is also proposed in the rat to attempt delineation of striatal cells activated by the sensorimotor cortex. In these experiments we propose (in AIM 3, with follow-up in the squirrel monkey in AIM 4) to use electrical and chemical stimulation of sensorimotor cortex to activate immediatearly genes in striatal neurons. The gene expression will be used as a cellular-level readout of neural ensembles activated by cortical input in the striatum and its output targets, and the pathways necessary for this activation will be determined. With these two complimentary techniques, our goal is to delineate the organization of corticostriatal sensorimotor maps in sufficient detail to gain insight into the functions of the striatum. The significance of this work is twofold. First, it may help uncover the neural substrates of focal and

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somatotypically distributed banal ganglia movement disorders. Second, it should help identifying what transformations occur in cortical-basal ganglia loops. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL NEUROANATOMY OF MOVEMENT DISORDERS Principal Investigator & Institution: Brown, Lucy L.; Associate Professor; Neurology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAY-2007 Summary: (provided by applicant): Although the gene for Huntington's disease (HD) has been identified, the processes that lead to cell pathology and degeneration are still unclear. The proposed studies examine early pathology and pathophysiology in two transgenic mouse models of Huntington's disease. Our preliminary data in one mutant model, the reversible HD94 model, suggest that the chemoarchitecture of the striatum is altered in early symptomatic stages of the disease: there are more mu opioid receptorrich striosomes in mutants than in controls, which may lead to an imbalance of activity between the striosome and matrix compartments and produce the symptoms of chorea and involuntary activity. The studies will determine whether there are more striosomes in mutants by using immunocytochemical methods to identify striosomes. The working hypothesis states that the early stages of the disease are associated with abnormal developmental processes. The specific hypothesis is that a critical part of the pathology underlying the symptoms and final degenerative process of Huntington's disease is abnormal neurogenesis prenatally and postnatally, and that the number of striosomes in mutants reflects neurogenesis abnormalities. In addition, our model of the behavioral functions of striosomes predicts that mutants will be more sensitive to dopamine agonists. Finally, the studies will investigate prenatal and adult cell proliferation and neurogenesis in mutants and their controls by using a thymidine analogue, bromodeoxyuridine (BrdU). The studies may provide clues to the function of the gene huntingtin, and define a target for therapeutic strategies. In addition, these studies address the plastic and proliferative capacity of the adult brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE-ENVIROMENT INTERACTION IN COGNITION Principal Investigator & Institution: Gilliam, T Conrad.; Borne Professor of Genetics and Developm; Genome Center; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2005 Summary: (provided by applicant): We propose a collaborative effort between Columbia University (CU) and University of Zulia (LUZ), Maracaibo-Venezuela, to investigate the effects of life conditions and environmental exposures together with genetic factors upon the expression of specific cognitive abilities. We aim to strengthen the capacity of Venezuelan scientists to design and execute research centered on cognitive impairment from birth to advanced age, with emphasis in disorders common in the State of Zulia; including Alzheimer's disease, Huntington's disease and Vascular Dementia. We propose the following specific aims for this exploratory project: 1. To assess the social impact of dementias in the State of Zulia. We will conduct a qualitative ethnographic study among family and caregivers of demented patients, as well as among primary care health professionals, identifying beliefs about cognitive impairment, dementia, knowledge, impact of disease on family life, self esteem, family identity, social reactions, access to health care and quality of care by professionals. 2. To assess current resources and needs and develop and initiate a plan to address these needs to promote the

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successful conduct of the proposed research and capacity building. 3. To show feasibility and generate preliminary data to justify submission of collaborative research via an R01 grant mechanism and to identify specific research questions that show the greatest promise for advancement. We will test whether a catecoI-O-methyltransferase (COMT) gene variant affects working memory and executive function in Venezuelan families segregating subcortical white matter hyperintensities. Variance accounted for by the gene variant and life conditions and environmental exposures will be examined. 4. To identify training and other capacity-building opportunities in the context of brain health promotion throughout life. At the end of the planning period, we hope to have initiated preliminary studies and to have organized, planned, prepared and assembled an application for a more comprehensive R01 grant involving collaboration between CU and LUZ investigators incorporating both research and capacity building. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MODEL OF NEURODEGENERATION Principal Investigator & Institution: Feany, Mel B.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2004 Summary: (Adapted from the application): Neurodegenerative diseases exact a massive toll on human and health care resources. They also pose the fundamental question of the mechanisms underlying selective degeneration of particular neuronal populations. Recent identification of the genes involved in several major neurodegenerative disorders, including Huntington's disease and Alzheimer's disease, represent major advances, but have not yet revealed how the encoded proteins produce cell death. Additional components of the neurodegenerative pathway must be identified. The applicants propose to use Drosophila as a model system to identify proteins required for neuronal degeneration. Both Huntington's disease and Alzheimer s disease are dominantly inherited neurodegenerative disorders most likely produced by toxic actions of the encoded gene products. Appropriate forms of both proteins will be expressed in Drosophila using the GAL4 system that facilitates transgene expression in a variety of defined tissue-specific and temporal patterns. The anatomic and behavioral abnormalities resulting from expression of the human transgenes will be characterized, and a phenotype suitable for generating second site suppressors and enhancers will be defined. Flies will then be mutagenized and genetic modifiers isolated. Mammalian homologues of these Drosophila modifiers will be human disease gene candidates and likely components of mammalian neurodegenerative pathways. The ability of many Drosophila proteins, including several discussed in the current application, to substitute functionally for their mammalian counterparts, suggests close analogies between the two systems. Even seemingly highly unique processes such as hindbrain compartmentalization and learning and memory show remarkable similarities. The basic cell biology of neurodegeneration should prove no exception. The applicant is an M.D./Ph.D. who will have completed a residency in anatomic pathology and subspecialty training in neuropathology prior to the proposed start date. She also holds a doctoral degree in neurobiology. The research will be carried out in a Drosophila laboratory group within the Harvard Medical School. A co-sponsor expert in human molecular genetics and neurodegenerative diseases has been selected to complement the primary laboratory's expertise in Drosophila molecular genetics and development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLUTAMATE TRANSPORTER REGULATION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Widnell, Katherine L.; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Glutamate transport is essential for the synaptic inactivation of the neurotransmitter glutamate. A family of glutamate transporters has been identified in both astroglia and neurons. These transporters play important roles in the pathophysiology of neurologic disorders, notably amyotrophic lateral sclerosis and stroke. GLT1 is a glutamate transporter localized on astrocytes. We have determined that in a murine transgenic model of Huntington's Disease (HD) expressing Nterminally truncated huntingtin (N I 7182Q), there are decreased levels of GLT1, but not other glutamate transporter subtypes, in the striatum. In this proposal, experiments are presented to study the possible role of GLT1 and other molecular transporter subtypes in the development of striatal cell pathology seen in HD. First, a technique for the establishment of organotypic striatal cultures will be developed. These cultures will provide the ability to manipulate conditions, assess factors that affect GLT1 expression, and monitor for excitotoxic changes. Second, in order to further assess the role of GLT1 downregulation, behavior and striatal histology will be examined after GLT1 anti-sense infusion into rat striatum. Third, the regulation of glutamate transporters in N17182Q transgenic mice will be further evaluated in various brain regions and at various time points related to behavioral and histologic abnormalities. Human tissue from HD postmortem brains will also be evaluated. The effect of upregulation of the GLT1 transporter subtype by the neurotrophin glialcell linederived neurotrophin (GDNF), and by the neuroinimunophilin GPI1046, will be evaluated in organotypic striatal cultures, and in vivo in transgenic HD mice. Finally, an EAAT2 (GLT1) overexpressing mouse will be crossed with transgenic mouse models of HD to determine if GLT1 over-expression can reverse some of the observed behavioral or pathologic phenotypes of HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HUNTINGTON AND VESICLE TRANSPORT Principal Investigator & Institution: Difiglia, Marian; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 15-AUG-1998; Project End 31-JUL-2002 Summary: Huntington's disease causes motor and cognitive dysfunctions, the degeneration of striatal and cortical neurons in the brain, and death of its victim within 15-20 years. The genetic mutation is an expanded region of polyglutamines at the Nterminus of huntingtin. The function of wild-type huntingtin and the mechanism of HD pathogenesis caused by mutant huntingtin are unknown. We have observed an abnormal accumulation and transport of huntintin in affected neurons of the HD brain. Similar patterns of mutant huntintin accumulation appear in clonal striatal cells transfected with cDNAs encoding huntingtin with an expanded polyglutamine region. Published studies and our preliminary observations suggest that wild-type huntingtin may function in receptor- mediated endocytosis. Mutant huntintin, like wild-type huntingtin, associates with clathrin-enriched membranes. Our overall hypothesis is that mutant huntintin causes neuronal dysfunction through its direct effects on receptormediated endocytosis and by its abnormal accumulation and transport. We propose a series of studies in clonal striatal cells to explore wild-type huntingtin's association with endosomes (Aimsl), to analyze the consequences of polyglutamine expansion in

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huntintin on endocytic function (Aim 2), and to evaluate the subcellular compartments that accumulate mutant huntingtin and contribute to cell death (Aim 3). Our studies will include techniques in confocal immunofluorescence microscopy, immunogold/electron microscopy, subcellular membrane fractionation, immunoisolation and Western blot. The results will identify the subcellular processes involved in HD pathogenesis and will lead to a rational strategy for treatment of this devastating disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUNTINGTON DISEASE IN VENEZUELA AND OTHER STUDIES Principal Investigator & Institution: Wexler, Nancy S.; Higgins Professor of Neuropsychology; Hereditary Disease Foundation 1427 7Th St, Ste 2 Santa Monica, Ca 90401 Timing: Fiscal Year 2001; Project Start 01-APR-1985; Project End 31-JUL-2002 Summary: (Investigator's Abstract): Through the study of a unique Venezuelan Huntington's disease kindred the gene for HD was localized to chromosome 4p using new molecular genetic techniques; homozygotes for the disease were identified "and the phenomenon of complete dominance" genetically documented for the first time in human medical genetics; key genetic recombinants were found, permitting more precise chromosomal localization of the HD gene and high resolution geneiic and physical mapping of the candidate region; and the HD gene itself was discovered to be an unstable trinucleotide CAG repeat in a novel protein called "huntington." The Venezuelan kindred now has an unparalleled role to play in this next phase of understanding the disorder, from the molecular behavior of the repeat to its clinical manifestations. It is the only existing kindred in which the HD allele has been inherited from a progenitor and passed through ten generations and hundreds of meioses, eliminating allelic heterogeneity and ensuring that all those in the kindred who have inherited the HD gene have the identical allele and terrain surrounding it. The enormity of the kindred, over 14,000 people, the huge sibship size, the shared background genes and environment, and the cooperativity of family members provide an unmatched research resource. The aims of the project are: 1 ) To understand the relationship between genotype and phenotype in their natural habitat, unbiased by ascertainment. To study the behavior of the CAG repeat segregating on a single haplotype as it has already afflicted over 400 people and as it now threatens 4,697 at risk children, 1,653 of whom will die of the disease in the ensuing years. To learn how genetic characteristics contribute to clinical consequences and seek to explain why people with the same number repeat units have widely varying clinical manifestations. 2) To discover modifiers, either genetic or environmental, that may regulate the frequency or magnitude of CAG expansion or influence phenotypic expression. 3) To analyze juvenile cases in more detail and the fathers who produce them; to understand what governs the plasticity of the repeat and why huge expansion produce juvenile onset. 4) To characterize genetically and phenotypically the growing population of homozygotes and learn how they cope with two doses of expanded alleles. The Venezuelan HD kindred is the largest single source of these rare homozygous individuals in the world; 8 have been identified already and 28 should be in the kindred. 5) To collect tissue samples that can provide insight on the expansion process, including lymphoblast lines and sperm samples. As a prospective, longitudinal study, to examine the effect of age, disease duration, birth order or environmental factors on sperm, in which mosaicism has been identified. 6) To collect brain and other post-mortem tissues from genetically and clinically well characterized members of the kindred to understand how the huntington protein specifically devastates striatal neurons. These tissues will enable us

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to tie together the behavior of the gene, its target in the brain and the clinical repercussions these two produce. 7) To develop a molecular cognitive neuroscience approach to understanding how the expansion produces profound cognitive and behavioral disturbances. To develop a more precise neuropsychological battery to ascertain capacities and limitations that are germane to the underlying neuropathology. 8) To explore how psychiatric and cognitive symptomatology can also be regulated by the expanded repeat or some other genetic modifiers. 9) To characterize the kind-red for common disorders and genetic traits or markers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IN VIVO EFFECTS OF A LONG REPEAT IN THE HD GENE Principal Investigator & Institution: Detloff, Peter J.; Assistant Professor; Biochem & Molecular Genetics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-JUL-2002 Summary: The long term goal for this work is to determine the molecular basis of Huntington's disease (HD). The basis for this progressive neurological disorder is an expanded CAG repeat in the Huntington gene that codes for a long polyglutamine repeat (11, 28, 51, 63, 69). The work proposed in this competitive renewal extends work completed during the first 2 years of funding during which the PI made a mouse with a 90 unit CAG repeat in the murine HD homolog (Hdh (CAG) 90). Recent work has shown the presence of Neuronal intranuclear inclusions (NIIs). The PI will also make mice with modifications of Hdh (CAG) 90 designed to enhance access of the polyglutamine-containing portion of the mutant protein to the nucleus. The PI will assess the role these modifications play in the formation of NIIs and the possible role NIIs play in causing abnormalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHIBITION OF FIBRILLOGENESIS WITH B-STRAND MIMICS Principal Investigator & Institution: Hammer, Robert P.; Associate Professor; Chemistry; Louisiana State Univ A&M Col Baton Rouge Office of Sponsored Programs Baton Rouge, La 70803 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Application). Several age-associated degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease are characterized by the formation of fibrillar structures called amyloid plaques. The long-range goal of this work is to develop inhibitors of amyloidogenesis and to test whether or not such "blocker" molecules can be effective suppressors of toxicity and ultimately therapeutic agents for amyloid associated diseases. The specific aims and the hypotheses to be tested are: (1) Design and synthesis of new B-strand mimics that block the fibril and protofibril formation of the Alzheimer-associated B-amyloid peptide (All). Oligomerization of B-sheet structures, like those in A-Beta fibrils, can be inhibited or reversed by extended peptide structures that have only one edge available for hydrogen bonding. (2) Determination of the inhibition mechanism of protofibrillogenesis with Bstrand mimics. Potentially neurotoxic protofibril formation can also be inhibited by "blocker" molecules, the formation and dissolution of A-Beta protofibrils in the presence and absence of molecules known to inhibit fibril formation will be studied using scanning force microscopy (SFM), static light scattering (SLS), dynamic light scattering (DLS), analytical ultracentrifugation (AU) and fluorescence photobleaching recovery

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(FPR). (3) Detection of early intermediates in protofibril assembly by fluorescence photobleaching recovery (FPR) and AU and determination of molecularity of these early intermediates. Early aggregates can be dissociated in the presence of p-strand mimics. (4) Initiation of fibrillogenesis on hydrophobic and hydrophilic surfaces. Formation of protofibrils and fibrils of A-Beta in vivo is the result of interactions between soluble ABeta and various moieties on the surface of neuronal cells and "surface-induced" or nucleated A-Beta polymerization can be stopped or reversed by the presence of B-strand mimics. The potential impact of this work is gaining a better understanding of the etiology of AD and development of pharmaceutical agents for treating AD and other amyloid diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRABODY THERAPY OF PARKINSON'S DISEASE Principal Investigator & Institution: Messer, Anne; Director/Research Scientist; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2004 Summary: (provided by applicant) This proposal seeks to develop engineered intracellular antibodies (intrabodies) as novel potential clinical reagents and drug discovery tools for the treatment of Parkinson's disease (PD). Intrabodies make use of the specificity of antibodies to form complexes with intracellular proteins, and are already in clinical trials for treatment of cancers and AIDS. Recently, we published the first application of this powerful technology to a neurodegenerative disease, showing that human single-chain Fv intrabodies, selected from a phage display library, can counteract in situ Huntington aggregation in cellular models of Huntington's Disease (HD). By choosing an epitope adjacent to the abnormally folding expanded polyglutamine of the HD protein, we can alter the abnormal protein-protein interactions that characterize the mutant protein. Parkinson's Disease brains show formation of filamentous intracellular inclusions (Lewy bodies) as their most striking pathology. These appear to be composed of abnormally aggregated alpha-synuclein in both sporadic and hereditary forms of the disease. The alpha-synuclein protein data to date suggest several candidate target sequences that might prevent misfolding of synuclein, or be used to clear abnormal material in Parkinson's cells. We propose to select antisynuclein single-chain Fv intrabodies against unique, defined domains and forms of asyn, using human phage display libraries. These will then be tested for their capacity to reverse reported physiological defects in model systems. Models will include several that over-express wild-type alpha-synuclein to mimic sporadic P.D: transient transfections in cell lines and brain slice cultures, moving on to transgenic Drosophila and eventually transgenic mice. All of these studies will take advantage of the technologies and expertise coming out of the HD studies, which are actively and successfully ongoing in the lab. Long-term goals include administering these antibody reagents via gene therapy vectors, or as stable, multi-functional proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ION CHANNEL DYSFUNCTION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Cantrell, Angela R.; Assistant Professor; Anatomy and Neurobiology; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008

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Summary: (provided by applicant): It has recently been suggested that neuronal degeneration may occur as a secondary phenomenon in response to neuronal dysfunction in HD. In support of this idea, recent reports have indicated that electrophysiological abnormalities occur in the brains of HD transgenic animals. These abnormalities include altered somatic discharge, broadening of the excitatory postsynaptic potential and failure to induce long term potentiation following high frequency stimulation. These abnormalities precede neurobehavioral and neuropathological alterations suggesting to some researchers that cytoplasmic functions including neurotransmitter regulation of ion channels and regulation of intracellular Ca2+ may play a role in this disease. If this is in fact the case, then understanding neuronal dysfunction in HD may be critical to the development of rational treatment strategies and early intervention programs. An extrinisic mechanism such as glutamate excitotoxicity has been proposed to account for the ultimate degeneration of medium spiny neostriatal neurons, therefore, we hypothesized that changes in the membrane properties of the cortical projection neurons which provide input to the medium spiny neostriatal neurons might be important in HD. This idea, while intriguing, has not been fully investigated using the newly available animal models of HD. We present preliminary data to support this idea and demonstrate that electrophysiological abnormalities occur in the presynaptic corticostriatal projection neurons in HD transgenic mice. Since the electrical activity of a neuron is regulated by its own intrinsic cytoplasmic properties as well as its synaptic inputs, it will be important to conduct a thorough study of these alterations in the electrophysiological properties of the presynaptic cortical projection neurons in HD. These electrophysiological abnormalities in corticostriatal projection neurons may contribute to neuronal dysfunction and the subsequent neuropathology observed in HD. This hypothesis will be tested in acutely isolated, identified cortical projection neurons obtained from HD mouse models in which expression of mutant huntingtin has been induced. Techniques employed include patch-clamp recording methods, single-cell RT-PCR and immunohistochemistry. This proposal has 3 Specific Aims: 1) To define the physiological properties of pharmacologically isolated HVA Ca2+ channels, voltage-gated Na+ channels and voltage-gated K+ channels in acutely isolated corticostriatal projection neurons from HD transgenic mouse models. 2) To determine the molecular mechanisms underlying the observed increase in HVA Ca2+ channel activity in corticostriatal neurons from R6/2 transgenic mice. 3) To expand our studies to include other classes of cortical projection neurons. These studies will provide valuable information for the elucidation and treatment of a variety of motor deficits and neurodegeneration observed in HD and a host of other neurological disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONGITUDINAL STUDIES AMONG AT-RISK HD GENE CARRIERS Principal Investigator & Institution: Foroud, Tatiana M.; Associate Professor; Molecular and Medical Genetics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) To identify and quantify changes among presymptomatic Huntington disease gene carriers who had not yet developed definite chorea, we performed the largest, study of individuals at-risk for HD (n=657) Subtle abnormalities in oculomotor, extrapyramidal and pyramidal motor, and cognitive measures were identified. We propose to reexamine this unique sample of at-risk individuals using an expanded test battery that includes more sensitive and specific

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quantitative measures for each subset of variables for which significant differences between presymptomatic gene carriers and nongene carriers were initially observed. These new measures increase the power of our proposed longitudinal studies of the rate of change among presymptomatic gene carriers as they approach the manifestation of clinically diagnosable HD. These novel studies are designed to: 1) Further delineate the deficits observed in the subclinical and early symptomatic phase of disease; 2) measure the rate of increasing abnormality among presymptomatic gene carriers; 3) investigate the interrelationships among the variables so as to identify measures with similar rates of deterioration, which might suggest common pathways affected early in the disease process; 4) quantify the relationship of CAG repeat number with disease onset and progression. The results of these studies will improve the understanding of the presymptomatic and early symptomatic phase of HD allowing for earlier diagnosis and identify subclinical biomarkers that can be utilized in clinical trials to evaluate therapeutic agents designed to slow progression and delay the onset of clinical HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ATAXIN-1 MEDIATED PURKINJE CELL DEATH Principal Investigator & Institution: Vig, Parminder J.; Neurology; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Spinocerebellar ataxia-1 (SCA-1) belongs to a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene product ataxin-1. One of the major cell types affected by ataxin-1 is the cerebellar Purkinje cell. The mechanism by which ataxin-1 causes Purkinje cell degeneration in SCA-1 is not known, however, ataxin-1 down regulates Purkinje cell specific proteins involved in calcium homeostasis and signaling in patients with SCA-1, and in presymptomatic SCA-1 transgenic mice. Therefore, the present proposal is designed to determine if targeted deprivation of one of the specific proteins involved in calcium homeostasis will further enhance ataxin-1 toxicity and if trophic upregulation of this protein will rescue SCA-1 Purkinje cells from degeneration. The long-term goal of this project is to understand the role of calcium signaling pathways in neuronal degeneration in order to design therapeutic approaches in clinical management of SCA-1 and other dominantly inherited cerebellar ataxias. To determine if decreased expression of calcium binding protein calbindin-D 28k (CAB) will increase the toxic effects of ataxin-1 on Purkinje cells, double mutant mice will be generated by mating CaB null mice with SCA-1 transgenic mice. To determine if overexpression of insulin-like growth factor - I (IGF-I) will rescue SCA-1 Purkinje cells from degeneration, double mutant mice will be generated by mating mice overexpressing IGF-I with SCA-1 transgenic mice. The changes in Purkinje cells will be assessed by behavioral, biochemical, immunochemical and immunohistochemical methods, focusing on the alterations in the expression of Purkinje cell markers, calcium binding proteins, and proteins involved in calcium signaling. Purkinje cells cultured from 0-1 day old SCA-1 transgenic mice will be used to determine if cultured Purkinje cells expressing mutant ataxin-1 show (i) altered expression of calcium binding proteins and proteins involved in calcium signaling (ii) sensitivity to increased Ca 2+-influx (iii) altered response to the inhibitors of calcium-dependent proteases and (iv) if treatment with IGF-I can reverse ataxin-1 mediated pathological changes. Purkinje cell cultures from non-transgenic mice will be used as controls. Complementary analysis to compare changes in cultured Purkinje cells with those cultured from CaB null and transgenics with Huntington's disease will also be performed. Further, changes observed in SCA-1

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patients and in transgenic mice will be compared with that in Machado-Joseph disease/SCA-3, other cerebellar ataxias and normal controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF GENE DYSREGULATION IN HD Principal Investigator & Institution: Olson, James M.; Assistant Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: (Adapted from applicant's abstract): Several lines of evidence suggest that mutant huntingtin affects gene transcription by sequestering transcription activating and repressing proteins. This does not explain the gene expression changes that occur before mutant huntingtin is detectable in the nucleus, nor does it account for transcription changes caused by abnormal signaling from damaged afferent neurons. The overall aim of this application is to test the hypothesis that the earliest gene expression changes in Huntington's disease (HD) reflect a response of the neuron to misfolded huntingtin protein and to abnormal signaling between afferent and target neurons. To accomplish this the investigator proposes two Specific Aims 1) use mice and cell culture models that express mutant huntingtin protein in eitherthe nucleus orthe cytoplasm to determine how cells transcriptionally respond to each and 2) use mice that express mutant huntingtin protein in eitherafferent neurons ortarget neurons to determine transcriptional responses in neurons. The transcriptional responses will be correlated with pathogenic changes that occur in response to the transgenes. This will generate information and tools needed to further model and test early processes in Huntington's disease. Our long-term goal is to identify early pathogenic events in Huntington's disease in order to provide rational targets for the development of prophylactic drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF LONG-TERM DEPRESSION IN THE STRIATUM Principal Investigator & Institution: Kreitzer, Anatol C.; Psychiatry and Behavioral Sci; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Long-term changes in synaptic strength are thought to represent a cellular correlate of learning and memory. In the hippocampus, long-term potentiation (LTP) and long-term depression (LTD) have been studied extensively, and a number of different mechanisms have been elucidated, some of which coexist at the same synapses. In the striatum, changes in synaptic function are thought to correlate with behaviors such as habit formation, as well as with pathologies such as Parkinson's and Huntington's disease and drug addiction. However, the mechanisms, or even the types of plasticities present at these synapses, have not been fully described. The goal of this research proposal is to examine LTD in both the dorsal striatum and its ventral extension, the nucleus accumbens. A number of studies have found various and conflicting results regarding LTD in these areas. To examine the types of LTD present at synapses in both dorsal striatum and nucleus accumbens, various induction protocols and experimental paradigms will be tested. Specific mechanisms of LTD induction and expression will then be studied using electrophysioiogical recordings combined with molecular techniques such as viral-mediated gene transfer. These studies will provide a framework for understanding how long-term changes in synaptic strength in the striatum are related to such health issues as addiction and neurodegenerative disease.

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

Project Title: MECHANISMS OF MOTOR LEARNING IN NEUROLOGICAL DISEASE Principal Investigator & Institution: Krakauer, John W.; Assistant Professor; Neurology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: The proposed award is designed to develop the candidate's clinical research skills to prepare him for a career as an independent investigator in the application of motor psychophysics and functional brain imaging to the study of neurological disease. Research Plan: Stroke, Huntington's disease (HD), and Idiopathic Torsion Dystonia (ITD) are diseases that rob people of motor function in the prime of life. Many of the measures of motor performance and functional status commonly used in clinical trials and rehabilitation suffer from subjectivity and lack of scientific validation. The first goal of the proposed study is to characterize and quantify the motor deficit in these diseases using methods previously developed in the study of arm movements in normal subjects. In particular, we will emphasize the importance of examining motor learning abnormalities because we hypothesize that these will give a direct measure of a patient's capacity to compensate or recover from neurological disease. The second goal is to correlate psychophysical parameters of motor performance and motor learning to the degree of expression of brain networks as revealed by functional imaging. This will provide considerable insight into the brain mechanisms underlying abnormalities in motor control. HD and ITD each have an established genetic basis allowing asymptomatic carriers to be identified. Our preliminary studies indicate that these subjects have psychophysical and network abnormalities even though more conventional assessments fail to find any evidence of neurological disturbance. If we confirm and extend these observations, then we will have the tools to follow therapeutic intervention at the earliest stages of disease. In the long term, we hope that our work will lead to the development of a battery of motor tasks that, in conjunction with functional imaging, will be applicable to any neurological disease. This battery will quantify motor deficits; allow monitoring of therapy; provide insight into brain mechanisms: and may serve a rehabilitative function. Educational Plan: By completing this project, I will accomplish six main educational objectives: (1) The design and application of motor psychophysics to neurological disease; (2) Learning PET imaging techniques; (3) The development of skills in brain network analysis and modeling; (4) Learning advanced statistical methods; (5) Learning the principles of functional magnetic resonance imaging; (5) Learning to conduct ethical scientific research, collaborate with colleagues, and produce high quality presentations and publications; and (6) Learning to place experimental findings within their clinical context, and relate them to clinical assessments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METABOTROPIC NEURODEGENERATION

GLUTAMATE

RECEPTORS

IN

Principal Investigator & Institution: Young, Anne B.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 15-AUG-1995; Project End 31-JUL-2005 Summary: Description (From the applicant's abstract): Human neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's

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disease (HD) and amyotrophic lateral sclerosis (ALS) are characterized by adult onset, progressive neurologic dysfunction, and a paucity of effective therapies. These common disorders produce substantial disability, and their importance to public health is expected to increase as the population ages. One or more causative genes have now been isolated for familial forms of each of these four devastating neurologic illnesses, making possible the development of transgenic mouse models. Although such animals now exist, the exact mechanisms by which mutant genes cause neurologic disease remains unclear. Unless the etiologic mechanisms underlying the neurodegenerative diseases are clearly identified, rational therapeutic interventions will be impossible. The neurotransmitter glutamate has been implicated as a causative factor in the etiology of neurodegenerative disorders. Specifically, one class of glutamate receptors, the metabotropic glutamate receptors (mGluRs), may be specifically abnormal in many of the neurodegenerative disorders. This project will examine metabotropic glutamate receptors in transgenic mouse models of AD, PD, HD, and ALS using ligand binding, in situ hybridization, immunohistochemistry, and Western blotting. Alteration of mGluR expression level is also predicted to have direct implications for the abnormal synaptic functioning which is characteristic of neurodegenerative diseases. Thus, we will also explore glutamate-related intracellular signaling pathways in the brains of transgenic mice. Finally, if mGluR dysfunction is an important part of disease etiology, drugs targeting mGluRs may ameliorate symptoms in certain of these models. We will test if administration of mGluR-active medications improves clinical outcome in mouse models of these diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF CASPASE PATHWAYS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Friedlander, Robert M.; Associate Director; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: The interleukin-1beta converting enzyme (caspase-1 or caspase-1) cell death gene family, also known as the caspase family, plays an important role in apoptosis. Evidence indicates that caspase- 1 is involved in mediating brain damange in ischemia, trauma, and in amyotrophic lateral sclerosis. We have evidence implicating caspase-1 as an important mediator of cell dysfunction and disease progression in Huntington s disease (HD). The broad objective of this project is to evaluate the mechanisms of caspase-1-mediates disease progression in HD. Preliminary results indicate that caspase1 is activated in human and mouse HD brain specimens. In addition, inhibiting caspase function slows the progression and delays the mortality in a mouse model of HD. The specific aims are: 1) evaluate the expression and activation status of different members of the caspase family in human and mouse HD brain specimens, 2) evaluate the role of mature IL-1beta, a product of caspase-1 activation, in the pathogenesis of HD, 3) determine whether bc1-2 might be a neuroprotector in HD, and whether its effects might be synergistic with caspase-1 inhibition, 4) evaluate pharmacological approaches to slow the progression of HD, and 5) evaluate the mechanism of inhibition of weight loss in HD mice by caspase-1 inhibition, 6) evaluate the impact of HD on neural stem cell proliferation and differentiation. Significance: To elucidate the mechanistic pathways by which caspase-1 mediates disease progression and death in HD. Since caspase-1-mediated cell death is a common pathway shared by a variety of neurological disorders, understanding the mechanistic pathways mediating neurodegeneration in

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HD should provide important information for the development of treatments for diseases sharing this cell death pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETIC APPROACHES TO LEARNING AND MEMORY Principal Investigator & Institution: Tonegawa, Susumu; None; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2001; Project Start 06-SEP-1994; Project End 31-MAR-2006 Summary: (provided by applicant): The long-term objectives of this competing renewal are to apply conditional gene manipulation techniques developed for mice to the analyses of molecular, cellular, and neuronal ensemble mechanisms underlying hippocampus-dependent learning and memory. Using the molecular genetic methods developed in this laboratory, mouse strains will be generated in which the gene encoding the a isoform of Ca2+/calmodulin-dependent protein kinase-II (CaMKII), or the g or B isoform of protein kinase C (PKC) is deleted (knocked out) specifically and separately in CAl or CA3 pyramidal cells of the hippocampus. Several transgenic mice will be generated in which the CaMKII inhibitor protein (CaMKII-IN) is overexpressed specifically in CAl or CA3 pyramidal cells, or a dominant negative form of Ca2+/calmodulin-dependent protein kinase-IV (dnCaMKIV) is overexpressed in the forebrain. The issue of whether expression of long term potentiation (LTP) at Schaffer collateral CAl synapses is based on a pre- or postsynaptic mechanism will be examined by subjecting the CAl- or CA3- specific CaMKII knockout, PKC knockout and CaMKIIIN transgenic mice to electrophysiological analysis of brain slices. This study will also examine whether LTP underlies learning and memory by analyzing the CAl-specific alphaCaMKII knockout, CAl-specific CaMKII-IN transgenic, and the forebrain-specific CaMKIV transgenic mice with electrophysiological and behavioral methods. Furthermore, the role of CaMKIV in different phases of the mnemonic process, namely acquisition, consolidation, and retrieval of memory, will be assessed by analyzing dnCaMKIV transgenic mice in which the level of expression of dnCaMKIV can be reversibly controlled. It is proposed to identify and characterize genes that are activated in the CAl region upon the formation of a long term memory by combining mouse genetics technology developed in this laboratory with DNA chip and DNA microarray technologies. Finally, it is proposed to study roles of CA3 NMDA receptors and the CA3 recurrent network in learning and memory, and in the formation of memory representation in the hippocampus by creating CA3-specific NMDA receptor knockout mice and subjecting them to a variety of memory tasks and to in vivo multielectrode recordings, respectively. The knowledge gained from these studies will constitute the basis for developing diagnostic and therapeutic methods for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease as well as for the development of learning enhancement methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MECHANISMS OF AXONAL TRANSPORT Principal Investigator & Institution: Brady, Scott T.; Professor and Head; Cell Biology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-JUL-1986; Project End 31-AUG-2005 Summary: (From the Applicant's Abstract): Understanding axonal transport processes is a key to understanding the dynamics of the nervous system, because they underlie

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neuronal growth, maintenance and regeneration. As a result, elucidation of molecular mechanisms for fast axonal transport can provide essential insights into the function and pathology of the nervous system. Functions as diverse as conduction of the action potential, release of neurotransmitter, creating and sustaining the presynaptic terminal, neuronal development and regeneration, and maintenance of neuronal architecture depend critically on fast axonal transport of membrane bounded organelles (MBOs) along microtubules. Similarly, disruption of fast axonal transport has been implicated in pathogenesis for a wide range of neuropathological conditions, including diabetic and toxic neuropathies, motor neuron disease (ALS and others) and degenerative diseases of the nervous system (Huntington's disease and others). Our original studies of fast axonal transport in isolated axoplasm from the squid giant axon led to discovery of a new family of mechanochemical ATPases: the kinesins. Kinesins are motors for movement of membrane bounded organelles in the anterograde direction of fast axonal transport. Previous work supported by this application answered many questions about the biochemistry and molecular biology, cell biology, and neurobiology of kinesin. Future experiments will extend our current studies on molecular mechanisms of fast axonal transport in three areas. First, we propose that physiological properties of different kinesins are determined by variation within specific functional domains among kinesin isoforms of the neuron. Studies proposed in this application combine methods from biophysics, cell biology, and molecular biology to delineate the functional architecture of neuronal kinesins and determine physiological functions for each domain. Second, specificity of kinesin interactions with different organelles suggest that kinesin isoforms are uniquely targeted to specific classes of MBOs through a combination of specific membrane receptors and general kinesin interacting proteins. Proposed experiments will identify kinesin receptors and interacting proteins in nervous tissues. Finally, kinesins are subject to posttranslational modifications in neurons that vary among the different isoforms. We propose that posttranslational modifications of kinesin serve to regulate kinesin function in neurons. Pathways associated with these modifications may control kinesin interactions with specific classes of MBOs as well as kinesin-mediated motility and ATPase activity. Planned experiments will determine the functional significance of posttranslational modifications on kinesin heavy and light chains, as well as defining relevant regulatory pathways. The proposed studies will help us understand the role of the kinesins in both normal neuronal function and neuropathology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOTOR LEARNING AND MEMORY IN HEALTH AND DISEASE Principal Investigator & Institution: Shadmehr, Reza; Biomedical Engineering; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 31-MAR-2007 Summary: (provided by applicant): When one moves their hand from one point to another, the brain guides the arm by relying on neural structures that estimate physical dynamics of the task and transform the desired motion into motor commands. If our hand is holding an object, the subtle changes in the dynamics of the arm are taken into account by these neural structures and this is reflected in the altered motor commands. These observations have suggested that in generating motor commands, the brain strongly relies on internal models that predict physical dynamics of the external world. The internal models are learned with practice, and appear to be a fundamental part of voluntary motor control. However, we know very little about which neural structures in the brain are involved in formation of internal models for motor control and how they

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learn to represent these models. Our aim here is to combine behavioral and mathematical tools to infer how humans learn internal models, and how the process is affected when there is damage to specific motor structures in the brain. We approach the problem by considering a task where physical dynamics of reaching movements are altered. As people practice the task, we ask how did an error that was experienced in a given movement affect subsequent movements? We arrive at a generalization function that mathematically describes how the brain changes the internal model in response to an error. The shape of the generalization function predicts the receptive field of the elements that took part in representing the internal model with respect to movement kinematics. We study these generalization functions in position, velocity, and acceleration space of the arm. Preliminary results demonstrate a remarkable similarity between these behaviorally inferred bases and typical tuning properties of cells in the primary motor cortex. This suggests that tuning properties of these cells might be reflected in human behavior in the way that we learn and generalize patterns of force. We extend the studies to include generalization from one arm to the other. We further extend the studies to movements where dynamics are not dependent only on arm kinematics, but also on other cues: external cues where dynamics are linked to an arbitrary spatial or color cue, internal cues where dynamics depends on position of a movement with in a sequence. We compare how damage to the brain in Huntington's disease vs. cerebellar disease affects this learning. However, motor memories are not static. Their functional properties change within hours after a task is learned. We ask how this change affects the generalization function. Is the brain different in the way it responds to an error after a memory has consolidated vs. early in the learning phase? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MTDNA DAMAGE AND APOPTOSIS IN NEURODEGENERATION Principal Investigator & Institution: Ayala-Torres, Sylvette; Universidad Central Del Caribe Bayamon, Pr 009606032 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-DEC-2005 Summary: Many forms of neurodegeneration are associated with oxidative stress. Although the molecular mechanisms of neurodegeneration remain unknown, it has been proposed that the symptoms associated with several late-onset neurodegenerative diseases are the result of mitochondrial dysfunction and increased production of mitochondrial- generated reactive oxygen species (ROS). Preliminary studies using quantitative polymerase chain reaction show an age-associated increase in basal levels of mouse brain mitochondrial DNA (mrDNA) damage. We hypothesize that oxidative damage to mtDNA leads to a decline in mitochondrial function with concomitant increase in mitochondrial- generated ROS. The hypothesis predicts that impairment of mitochondrial function due to oxidative mtDNA damage can lead to neuronal apoptosis. Increasing evidence implicates apoptosis as a major mechanism of cell death in neurodegeneration is yet not known. This project will explore the molecular mechanisms of neuronal cell death by using the 3-nitropropionic acid (3-NPA) animal model of Huntington's disease. Recent evidence has suggested that 3-NPA, a mitochondrial neurotoxin, can lead to striatal apoptosis and neurodegeneration. is caused by an accumulation of mtDNA damage induced by oxidative stress. To test this hypothesis this application proposes: 1) to examine the association between mtDNA damage and apoptosis in mouse brain exposed to 3-NPA; 3) to examine the association between mitochondrial dysfunction and oxidative stress exposed to 3-NPA; 3) to determine the association between mtDNA damage, ROS production, and apoptosis in mouse striatum exposed to 3-NPA; and 4) to analyze the effect of inhibitors of caspases

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in mouse striatum on mtDNA damage, generation of mitochondrial ROS, and apoptosis after treatment with 3-NPA. This study will lead to a better understanding of the role of oxidative stress and mitochondria in apoptosis associated with neurodegeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MTOR ACTIVATION AND FUNCTION DURING CNTF SIGNALING Principal Investigator & Institution: Reeves, Steven A.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114

Assistant

Professor;

Timing: Fiscal Year 2003; Project Start 24-JUL-1998; Project End 31-JAN-2008 Summary: (provided by applicant): Signal transduction initiated by the neuroregulatory cytokine ciliary neurotrophic factor (CNTF) has been shown to promote neuronal survival in the injured or diseased nervous system. These findings have provided a basis for using CNTF as a therapeutic agent aimed at the treatment or prevention of a variety of neuropathological diseases, including amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, stroke, and several forms of cerebellar ataxias. The precise manner in which CNTF activates and coordinately regulates the signaling cascades it employs for its neuroprotective effects remains largely undefined. One important component in this cascade that we have recently identified is the mammalian target of rapamycin (mTOR). The TOR proteins have been shown to be key regulators of a diverse set of cell processes, and recent reports have indicated that mTOR may play a critical role in synaptic plasticity and memory. We hypothesize that mTOR is a critical link in one or more of the CNTF signal transduction pathways. Thus the research we are proposing in this application aims to determine the mechanism by which CNTF activates mTOR and to identify the role(s) that mTOR plays in CNTF-stimulated sympathetic neurons. This work could identify novel targets for therapies aimed at the treatment or prevention of a variety of central nervous system disorders as well as provide a sound scientific foundation for the clinical use of CNTF and CNTF analogues now being tested in clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NANOSCALE IRON PHASES IN NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Dobson, Jon P.; Keele University Keele St5 5Bg, England Keele, Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): AIMS:. To develop multi-modal imaging methods for high-resolution mapping of iron in neurodegenerative brain tissue. To examine the magnetic properties of neurodegenerative tissue for the possible presence of anomalous magnetic iron oxides. To examine the effects of biogenic, magnetic iron biominerals (primarily magnetite) on amyloid-beta aggregation in vitro. Research Design & Methods: The primary method for mapping iron distribution in tissue sections is via synchrotron x-ray scanning which will be conducted at Argonne National Laboratory. This technique will be used to identify iron anomalies eventually on a cellular level. And to compose composit images using a variety of imaing techniques. This work will enable correlation of iron anomalies and structural form to specific cellular and tissue structures for the first time. Examination of the magnetic properties of neurodegenerative tissue will be carried out pdmarily using Superconducting Quantum Interference Device (SQUID) magnetometry and Magnetic Force Microscopy (MFM). Using these methods the magnetic iron biominerals in the tissue will be characterized and compared to published data on non-pathologic and epileptic tissue samples. This

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will provide information on the relative abundance and type of magnetic iron biomineral present in the tissue and will help to either confirm or refute preliminary studies of nanoscale magnetic iron biominerals in Alzheimer's disease (AD) tissue. The effects of strong, local magnetic fields generated by nanoscale magnetic iron biominerals on amyloid-beta peptide aggregation rates will be examined using thioflavin-T assay and TEM imaging of peptide aggregates. Aggregation rates will be assessed in control solutions, solutions of peptide with coated magnetic nanoparticles and sham solutions containing the same concentrations of non-magnetic nanoparticles with the same size distribution and surface chemistry. Gla: FOREIGN GRANT: As the PI is a US citizen based at Keele University in the United Kingdom, the project will be administered through a foreign institution - Keele. The PI has considerable and unique experience in the analysis of magnetic iron biominerals in the brain (he has led all of the previous work described in this proposal) and is one of the few people in the wodd working in this field. The proposed project is highly interdisciplinary, incorporating aspects of biophysics, chemistry, neurobiology and biomedical engineering. The PI has a uniquely diverse background related to the proposed research, having worked in physics, chemistry and biomedical engineering departments and the UF Brain Institute since obtaining his PhD in 1991. He has published extensively in nanoscale magnetic iron biomineralization in the brain and his work has been featured by the media in such journals as Science,The Economist, Fact/Switzerland, The Los Angeles Times/Washington Post wire service as well as newspaper, radio and television coverage in six countries. The Pl's combination of skills and experience related to the research proposed here is unique and unavailable in the US. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURAL BASIS OF INSTRUMENTAL ACTION Principal Investigator & Institution: Balleine, Bernard W.; Assistant Professor; Psychology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 15-JAN-1997; Project End 31-DEC-2002 Summary: (Adapted from applicant's abstract): The organization of goal-directed action is influenced significantly by the agent's ability to inhibit or gate responses to sensory, motor and cognitive information. Deficits in these central inhibitory mechanisms are manifest in a number of neuropsychiatric syndromes characterized by disorders of 'voluntary' movement, e.g., Parkinson's disease, and intrusive involuntary movement, e.g., Tourette's syndrome and Huntington's disease. These cases make it clear that the capacity for goal-directed action is highly adaptive, indeed it is this capacity that allows us and other animals to control the environment in the service of our needs and desires. Nevertheless, although research into the physiological systems that subserve learning processes in humans and other animals has been of ongoing concern to the neuroscience research community, the neural basis of instrumental action is very poorly understood. The broad, long term objective of the current project is, therefore, to understand the neural mechanisms that control the learning and performance of goal directed or instrumental actions. Over the last decade striking advances have been achieved in the PI's understanding of the behavioral determinants of instrumental conditioning in animals. Specifically, instrumental performance has been found to reflect the integration of (I) representations of the relations between an action and its consequences; with (ii) representations of the incentive value of those consequences. Elegant but powerful behavioral procedures will be used to focus on the role of cortico-striatal interactions and feedback to cortex via pallidal and limbic structures on processes involved in the

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representation of the relation between an action and its consequences. In other experiments, the role of parallel interactions between insular cortex and basal forebrain structures in the representation of the incentive or 'goal' value of the instrumental outcome will be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROBIOLOGICAL PREDICTORS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Paulsen, Jane S.; Professor; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: The proposal is a longitudinal study of potential neurobiological and neurobehavioral markers of disease onset and progression in pre-symptomatic individuals who have the CAG expansion in the HD gene. A total of 500 subjects will be enrolled. Study subjects will be 30 to 55 years old and have a parental history of Huntington's disease. The study will enroll 425 cases with >39 CAG repeats (affected), and 75 controls with