Genetics and Molecular Biology Parkinsonism

描述(由申请人提供)：梅奥诊所的尤德尔帕金森病研究卓越中心是一个由神经学家、神经心理学家、遗传学家、神经病理学家和基础科学家组成的综合多学科研究计划，研究“帕金森氏症的遗传学和分子生物学”。该中心利用梅奥临床运动障碍科的临床优势和帕金森病(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，但拟议的研究具有高度的协同性。团队中的每一位成员都为任务带来了独特的知识和技能，我们在一起大于部件的总和。拟议的工作建立在十多年来一直在一起工作的非常成功和富有成效的核心之上。临床、遗传和病理资源几乎没有几个中心能与之匹敌。梅奥·尤德尔中心是尤德尔中心项目的独特补充。我们Udall中心的成功建立在建立成功的协作和慷慨的资源和数据共享的基础上。 这项提案的首要目标是更好地理解路易相关的帕金森病，这是帕金森病最常见的形式。路易小体也是DLB和帕金森病伴痴呆(PDD)的标志。PDD和DLB之间的关系尚不清楚，但帕金森病患者的这种非运动性并发症越来越受到帕金森病患者的关注。我们尤德尔中心的优势在于收集了大量的多事件PD家族，在发现PD基因方面取得了公认的成功记录，并在一个注释良好的脑库中收集了大量PD、PDD和DLB大脑。研究方案有三个项目和五个核心：项目1。“识别预测帕金森病发病、易感性和进展的遗传风险因素”(PL：Matthew J.Farrer，PhD)；项目2。“鉴定a-突触核蛋白聚集和细胞毒性的候选疗法”(公共部门：严淑惠博士)；项目3。核心B.临床(CL：Zbigniew K.Wszolek，MD)；核心C.Genetic(CL：Matthew J.Farrer PhD)；核心D.神经病理学(CL：Dennis W.Dickson MD)和核心E.教育和外展(CL：Ryan J.Uitti，MD)。 公共卫生相关性：帕金森病(PD)是导致神经性残疾的主要原因之一。通过遗传学研究了解其原因将导致动物和细胞培养模型开发帕金森病的治疗方法。随着帕金森病运动异常治疗的进展，人们对了解帕金森病的非运动特征越来越感兴趣，包括痴呆，这是研究的重点。 项目1 主要研究人员：马修·J·法雷尔，博士 标题：识别预测帕金森病发病、易感性和进展的遗传风险因素 描述(由申请人提供)：我们过去的Udall中心申请(2004-2009)提供了令人信服的遗传、基因组和生化证据，证明野生型a-突触核蛋白的过度表达是路易体疾病的主要风险因素。过去的基因发现立即改善了对罕见家族的诊断，并导致了针对a-突触核蛋白基因的RNA干扰的行业赞助的翻译计划。然而，OUR(PD、PDD、DLB和MSA)，以及α-突触核蛋白的作用还处于起步阶段。项目一有四个目标来解决S的这些问题：目标1对临床帕金森综合征和尸检证实的路易体病多发病家系进行外显子测序。正如我们的初步数据所表明的，所使用的方法提供了一种快速且经济有效的方法来识别疾病中的新基因突变(S)。目标2是对无核性疾病进行全面的SNCA基因组捕获和重新测序，以便能够对一系列路易体疾病的临床和病理表型进行比较遗传关联研究。我们需要确定影响疾病风险的精确变异及其分子机制。AIM 3的工作，使用特征最好的样本的子集，将从a-突触核病的全基因组转录组分析中提供补充数据。Lastiy，Aim 4将描述内源性miRNA在调节α-突触核蛋白表达中的作用。该项目不能离开一个中心完成；它在很大程度上依赖于核心B、C和D提供的资源和专业知识，并将互惠地为项目2和3的研究提供信息。我们的目标是提供有意义的分子诊断，以重新分类这种不同类型的疾病。我们的目标是通过基因发现从机制上了解路易体疾病的发病机制，并利用下一代测序方法的进展来研究α-突触核蛋白及其同源物。 公共卫生相关性：本项目在帕金森病患者家庭中发现的新的帕金森病基因将为了解帕金森病的病因提供一个窗口。由于α-突触核蛋白是帕金森病的主要蛋白质异常，因此对α-突触核蛋白基因变异的全面研究将为未来帕金森病的治疗提供新的方法。

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.