Identification of genetic risk factors that predict disease onset, susceptibility

我们过去的Udall中心应用(2004-2009)的工作提供了令人信服的遗传、基因组和生化证据，表明野生型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高效的方式来识别新的 疾病中的基因突变(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，并将相互促进项目2和3的研究。我们的目标是提供有意义的 分子诊断来重新分类这组不同的疾病。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。

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.