Genomic and Genetic Analysis of Parkinson's Disease

描述（由申请人提供）：帕金森病是最常见的与衰老相关的运动障碍，影响超过1.8%的65岁以上的个体。一种小蛋白，α-突触核蛋白，可能是罕见的家族性和常见的散发性疾病的发病机制的核心。 人α-突触核蛋白转基因果蝇忠实地复制了人类疾病的基本特征，包括多巴胺能神经元的年龄依赖性、进行性变性、路易体样包涵体形成和运动障碍。这种帕金森病的果蝇模型非常适合于衰老过程中的全基因组表达分析和导致多巴胺能细胞死亡的分子机制的强大遗传操作。 我们假设，α-突触核蛋白转基因果蝇的微阵列分析将确定控制神经变性的基因。我们将定义在α-突触核蛋白转基因中差异转录的基因， 果蝇在衰老和遗传验证一种新的抑制剂或增强剂的α-突触核蛋白病理。为此，我们将追求三个具体目标：1）我们将确定帕金森病果蝇模型中在渐进年龄段差异转录的基因。2)我们将从遗传学上验证一个优先级最高的微阵列衍生的候选修饰剂。3)我们将通过详细分析所涉及的通路来表征修饰α-突触核蛋白诱导的神经变性的机制。 老年人α-突触核蛋白转基因帕金森病的基因组学和遗传学联合分析 果蝇将确定一个基本的致病机制，并阐明新的治疗目标的人类疾病。果蝇修饰基因的哺乳动物同源物将成为人类帕金森病的候选易感基因。这些研究将扩大候选人在生物信息学方面的专业知识，并在哈佛医学院和布里格姆妇女医院的一流研究环境中提供果蝇遗传学方面的特殊培训。

DESCRIPTION (provided by applicant): Parkinson's disease is the most common aging-related movement disorder affecting more than 1.8% of individuals over age 65. A small protein, alpha-synuclein, might be central to the pathogenesis of both rare familial and common sporadic forms of the disease. Drosophila transgenic for human alpha-synuclein faithfully replicate essential features of the human disease including age-dependent, progressive degeneration of dopaminergic neurons, Lewy-body-like inclusion formation and movement disorder. This Drosophila model of Parkinson's disease is ideally suited for genome-wide expression analysis during aging and powerful genetic manipulation of molecular mechanisms leading to dopaminergic cell death. We hypothesize that microarray analysis of alpha-synuclein transgenic Drosophila will identify genes controlling neurodegeneration. We will define genes differentially transcribed in alpha-synuclein transgenic Drosophila during aging and genetically validate a novel suppressor or enhancer of alpha-synuclein pathology. To that end we will pursue three Specific Aims: 1) We will determine genes differentially transcribed at progressive ages in the Drosophila model of Parkinson's disease. 2) We will genetically validate a top priority microarray derived candidate modifier. 3) We will characterize the mechanism modifying alpha-synuclein-induced neurodegeneration by detailed analysis of the implicated pathway. The combined genomic and genetic analysis of Parkinson's disease in aging alpha-synuclein transgenic Drosophila will identify a fundamental pathogenic mechanism and elucidate novel therapeutic targets for the human disease. The mammalian homolog of the Drosophila modifier will be a candidate susceptibility gene for human Parkinson's disease. These studies will expand the Candidate's expertise in bioinformatics and provide exceptional training in Drosophila genetics in the superb research environment of Harvard Medical School and Brigham and Women's Hospital.