Expression Analysis and Genomic Convergence in PD

该项目的目标是使用我们称之为“基因组趋同”的多因子过程来识别和评估帕金森病（PD）的候选易感基因。该方法利用了许多不同类型的数据，包括基因组连锁分析、PD患者和对照组的基因表达谱、候选基因的生物活性、分子分析和基于家族的关联分析。PD患者有几个不同的脑组织受到严重影响：前嗅核是PD患者最先受到影响的组织之一，黑质在疾病过程中显示出多巴胺能神经元的急剧丧失，壳核的成像研究显示多巴胺和烟碱乙酰胆碱受体结合缺陷。在本项目中，我们将测量这些组织中的基因表达水平，以确定PD的候选易感基因。我们也会使用激光

The goal of this project is to identify and evaluate candidate susceptibility genes for Parkinson disease (PD) using a mulfifactorial process we have termed "genomic convergence." This approach utilizes a number of different kinds of data, including genomic linkage analysis, gene expression profiles in PD patients as well as controls, biological activity of candidate genes, molecular analysis, and family-based association analysis. Several different brain tissues are severely affected in PD patients: the anterior olfactory nucleus is one of the first tissues to be affected in PD, the substantia nigra shows dramatic loss of dopaminergic neurons over the course of disease, and imaging studies of the putamen show defects in dopamine and nicotinic acetylcholine receptor binding. In this project, we will measure the level of gene expression in these tissues in order to identify candidate susceptibility genes for PD. We will also use laser capture microscopy to identify candidate genes by measuring gene expression in three different cell types within the substantia nigra: the dopaminergic neurons, non-pigmented neurons, and astroglial cells. Together with Project III, we will examine gene expression in cybrid cultures. Differentially expressed genes will then be prioritized in a variety of ways. First, we will identify those that map to regions of PD linkage. Second, we will evaluate the biological activity of genes to find those that are consistent with known metabolic defects in PD. This process of convergence will greatly reduce the number of genes that must be evaluated. We will then identify single nucleotide polymorphisms (SNPs) within or nearby these prioritized genes. Taqman assays will be developed for each of these SNPs, and they will be transferred to Core C for genotyping and Project I for analysis. Genes that show association with PD or interactions with other genes or the environment will be evaluated further for their role in PD.