Expression Analysis and Genomic Convergence in PD

PD 中的表达分析和基因组趋同

• 批准号: 6812935
• 负责人: MICHAEL A HAUSER
• 金额: $ 29.08万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812935
• 关键词: Parkinson' s disease; bioinformatics; biotechnology; family genetics; gene expression; gene expression profiling; gene interaction; genetic markers; genetic polymorphism; genetic screening; genetic susceptibility; genetic transcription; glia; high performance liquid chromatography; human genetic material tag; laser capture microdissection; linkage mapping; microarray technology; neural degeneration; neurons; polymerase chain reaction; serial analysis of gene expression; single strand conformation polymorphism; substantia nigra

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.

该项目的目标是使用我们称为“基因组收敛”的多因素过程来识别和评估帕金森病 (PD) 的候选易感基因。该方法利用多种不同类型的数据，包括基因组连锁分析、PD 患者和对照的基因表达谱、候选基因的生物活性、分子分析和基于家族的关联分析。 PD 患者的几种不同脑组织受到严重影响：前嗅核是 PD 中最先受影响的组织之一，黑质在疾病过程中显示多巴胺能神经元的急剧丧失，壳核的影像学研究显示缺陷多巴胺和烟碱乙酰胆碱受体结合。在这个项目中，我们将测量这些组织中的基因表达水平，以确定帕金森病的候选易感基因。我们还将使用激光 捕获显微镜通过测量黑质内三种不同细胞类型（多巴胺能神经元、非色素神经元和星形胶质细胞）的基因表达来识别候选基因。我们将与项目 III 一起检查细胞培养物中的基因表达。然后，差异表达的基因将以多种方式进行优先排序。首先，我们将识别那些映射到 PD 连锁区域的区域。其次，我们将评估基因的生物活性，以找到与已知的帕金森病代谢缺陷一致的基因。这种收敛过程将大大减少必须评估的基因数量。然后，我们将鉴定这些优先基因内部或附近的单核苷酸多态性 (SNP)。将为每个 SNP 开发 Taqman 检测，并将其转移到 Core C 用于基因分型，Project I 用于分析。将进一步评估与帕金森病相关或与其他基因或环境相互作用的基因在帕金森病中的作用。