Genetics and Molecular Biology Parkinsonism

遗传学和分子生物学帕金森病

• 批准号: 8134123
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 11.63万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134123
• 关键词: Achievement; Administrator; Advisory Committees; Aging; Alzheimer' s Disease; American; Americas; Animal Model; Animals; Area; Autopsy; Award; Biochemical; Biological Assay; Biological Markers; Biological Models; Book Chapters; Boston; Brain; Calculi; Case Study; Cell Culture Techniques; Cell Line; Cell model; Cells; Cerebrovascular Disorders; Chad; China; Chromosomes, Human, Pair 17; Cities; Clinic; Clinical; Clinical Data; Cognition Disorders; Collaborations; Collection; Common Data Element; Communities; Complement; Complication; Consensus; County; Custom; Cytopathology; DNA; Data; Data Element; Data Set; Databases; Dementia; Development; Diagnosis; Diagnostic; Disease; Disease Association; Doctor of Philosophy; Drug Delivery Systems; Drug Formulations; Dystonia; Education and Outreach; Educational Activities; Enrollment; Eukaryotic Initiation Factor-4G; Europe; Evaluation; Exclusion Criteria; FTD with parkinsonism; Faculty; Family; Fellowship; Figs - dietary; Follow-Up Studies; Foundations; Foxes; Frontotemporal Dementia; Funding; Future; Gene Expression Profile; Gene Mutation; Generations; Genes; Genetic; Genetic Materials; Genetic Screening; Genome; Genomics; Germany; Goals; Grant; Histologic; Homologous Gene; Hong Kong; Human; Human Cell Line; Hypercapnic respiratory failure; Impaired cognition; Incidental Discoveries; India; Industry; Institutes; Institution; Interdisciplinary Study; International; Internet; Ireland; Israel; Japan; Knowledge; Korea; LRRK2 gene; Laboratories; Lead; Leadership; Lewy Bodies; Lewy Body Disease; Link; London; Longitudinal Studies; MPTP Poisoning; Medical; Medical Education; Medical center; Mental Depression; Mentors; Methods; MicroRNAs; Minnesota; Mission; Modeling; Molecular; Molecular Biology; Molecular Diagnosis; Molecular Genetics; Motor; Movement Disorders; Multiple System Atrophy; Mutation; Names; National Institute of Neurological Disorders and Stroke; Neuroblastoma; Neurodegenerative Disorders; Neurologic; Neurologist; Neurology; Northern Africa; Norway; Onset of illness; Operon; Outcome; Paper; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Pathogenesis; Pathologic; Patient Education; Patient Recruitments; Patients; Peer Review; Pennsylvania; Pharmacologic Substance; Phenotype; Phosphotransferases; Play; Poland; Positioning Attribute; Postdoctoral Fellow; Preclinical Drug Evaluation; Predisposition; Principal Investigator; Process; Productivity; Progress Reports; Progressive Supranuclear Palsy; Prospective Studies; Protein Binding Domain; Proteins; Proteomics; Publications; RNA Interference; Recruitment Activity; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Resource Sharing; Resources; Rest; Restless Legs Syndrome; Risk; Risk Factors; Role; SNCA gene; Saimiri; Sampling; Scandinavia; Scheme; Scientist; Series; Services; South America; Spain; Staging; Students; Subgroup; Sum; Support Groups; Syndrome; System; Taiwan; Targeted Research; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Uses; Time; Toxic effect; Training; Translating; Translational Research; Travel; Universities; Variant; Veins; Washington; Woman; Work; advanced disease; alpha synuclein; arm; base; brain research; brain tissue; candidate identification; clinical material; college; comparative; corticobasal degeneration; cost effective; cytotoxicity; disability; disorder risk; dynactin; early onset; gene discovery; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; illness length; improved; infancy; inhibitor/antagonist; insight; interest; kindred; leucine-rich repeat kinase 2; medical schools; meetings; member; molecular pathology; neuropathology; neurosurgery; next generation; novel; outreach; population based; posters; pre-clinical; pre-doctoral; prevent; programs; prospective; public health relevance; skills; small molecule; small molecule libraries; success; therapeutic target; viral gene delivery; web page

DESCRIPTION (provided by applicant): The Udall Center for Excellence in Parkinson Disease Research at the Mayo Clinic is an integrated, multidisciplinary research program of neurologists, neuropsychologists, geneticists, neuropathologists and basic scientists in the study of the "Genetics and Molecular Biology of Parkinsonism." The Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section and longitudinal studies of Parkinson disease (PD) and dementia with Lewy bodies (DLB) for the clinical material used in the research projects, as well as strong institutional commitment to PD research. The research proposed is highly synergistic despite the wide range of expertise and scientific background of the members of the Udall team. Each member of the team brings unique knowledge and skill sets to the mission, and together we are greater than the sum of the parts. The work proposed builds upon highly successful and productive cores that have been working together for over a decade. The clinical, genetic and pathologic resources are rivaled by few centers. The Mayo Udall Center is a unique complement to the Udall Center program. Success of our Udall Center has been based upon building successful collaborations and generous sharing of resources and data. This proposal has the overarching goal to better understand Lewy-related PD, which is the most common form of PD. Lewy bodies are also the hallmark of DLB and PD with dementia (PDD). How PDD and DLB relate to each other is unknown, but this non-motor complication of PD is of increasing interest to the Parkinson community. Strengths of our Udall Center are the large collection of multi-incident PD families, a proven track record of success in discovery of PD genes and a large collection of PD, PDD and DLB brains in a well annotated brain bank. The research proposal has three projects and five cores: Project 1. "Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD," (PL: Matthew J. Farrer, PhD); Project 2. "Identification of candidate therapeutics for a-synuclein aggregation and cytotoxicity," (PL: Shu-Hui C. Yen, PhD); Project 3. "Molecular pathology of Lewy-related cognitive dysfunction," (PL: Dennis W. Dickson, MD); Core A. Administrative (CL: Dennis W. Dickson, MD); Core B. Clinical (CL: Zbigniew K. Wszolek, MD); Core C. Genetic (CL: Matthew J. Farrer PhD); Core D. Neuropathology (CL: Dennis W. Dickson MD) and Core E. Education and Outreach (CL: Ryan J. Uitti, MD). PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is one of the leading causes of neurologic disability. Understanding its cause through genetic studies will lead to animal and cell culture models to develop treatments for PD. With advances in therapies for motor abnormalities in PD, there is increasing interest in understanding non-motor features of PD, including dementia, which is a focus of research. PROJECT 1 Principal Investigator: Matthew J. Farrer, Ph.D. Title: Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD Description (provided by applicant): Work from our past Udall Center application (2004-2009) provides compelling genetic, genomic and biochemical evidence that over-expression of wild-type a-synuclein is a major risk factor for Lewy body disease. Past genetic discovery has immediately improved diagnoses for rare families, and has lead to industry-sponsored translational programs in RNA interference targeting the a-synuclein gene. However, our (PD, PDD, DLB and MSA), and the role of a-synuclein is in its infancy. Project 1 has four aims to addr s these issues: Aim 1 Exonic sequencing of multi-incident family with clinical parkinsonism and autopsy confirmed Lewy body disease. As our preliminary data illustrates, the methods used provide a rapid and cost effective way to identify novel gene mutation(s) in disease. Aim 2 is for comprehensive SNCA genomic capture and re-sequencing of asynucleinopathies, to enable comparative genetic association studies of clinical and pathologic phenotypes across a range of Lewy body disorders. We need to identify the precise variants that influence disease risk, and their molecular mechanism. Work in Aim 3, using a subset of the best characterized samples, will provide complementary data from whole genome transcriptome analysis in a-synucleinopathies. Lastiy, Aim 4 will characterize the role of endogenous miRNA in the regulation of a-synuclein expression. The project could not be accomplished outside of a Center; it rests heavily on resources and expertise offered by Cores B, C and D, and will reciprocally inform research in Projects 2 & 3. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases. We aim to provide a mechanistic understanding of the pathogenesis of Lewy body disorders through gene discovery, and for a-synuclein and its homologues, exploiting advances in next-generation sequencing methods. Public Health Relevance: Novel Parkinson disease (PD) genes identified by this Project in families with PD will provide a window into the cause of PD. Since a-synuclein is the major protein abnormality in PD, a comprehensive study of variability in the gene for a-synuclein will lead to new future therapies for PD.

简介（由申请人提供）：梅奥诊所的尤德尔帕金森病卓越研究中心是一个综合的多学科研究项目，由神经学家、神经心理学家、遗传学家、神经病理学家和基础科学家组成，研究“帕金森病的遗传学和分子生物学”。该中心利用梅奥诊所运动障碍科的临床优势，以及帕金森病（PD）和路易体痴呆（DLB）的纵向研究，作为研究项目中使用的临床材料，以及对PD研究的坚定机构承诺。尽管Udall团队成员拥有广泛的专业知识和科学背景，但所提出的研究具有高度的协同作用。团队的每一个成员都为这项任务带来了独特的知识和技能，我们的团结比各个部分的总和更伟大。提议的工作建立在高度成功和富有成效的核心之上，这些核心已经一起工作了十多年。临床，遗传和病理资源是少数中心相媲美。梅奥尤德尔中心是尤德尔中心项目的独特补充。我们尤德尔中心的成功建立在建立成功的合作和慷慨的资源和数据共享的基础上。