Influence of genotype on microglia phenotype and function in PD

 描述（由申请人提供）：帕金森病（PD）是一种中枢神经系统（CNS）退行性疾病，其特征在于α-突触核蛋白的积聚和聚集，其中黑质的多巴胺能神经元死亡。先天免疫系统被认为在这些神经元的死亡中起作用。因此，我们假设小胶质细胞的基因型差异参与了PD的病理生理学，特别是这些多巴胺产生细胞的死亡。我们对来自健康年轻个体的数据进行的初步顺式eQTL分析表明，11个PD易感基因参与了骨髓细胞功能，其表达相对于每个风险等位基因在先天免疫细胞中发生了改变。 型单核细胞，而不是代表免疫系统适应性手臂的T细胞。因此，这些基因座代表了极好的候选者，作为将遗传风险因素与导致PD病理学改变的先天免疫功能联系起来的分子事件级联中的第一步。该项目的主要目标是：（1）确定髓样细胞中PD易感基因座干扰网络的组成基因;（2）了解其对小胶质细胞行为的功能影响;（3）研究这些易感基因座对CNS小胶质细胞活化和基因表达的作用。

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) characterized by the accumulation and aggregation of a-synuclein in which the dopaminergic neurons of the substantia nigra die. The innate immune system is thought to play a role in the demise of these neurons. Therefore, we hypothesized that genotypic differences in microglia are involved in the pathophysiology of PD and, particularly, in the death of these dopamine producing cells. Our preliminary cis-eQTL analyses of data from healthy young individuals have implicated 11 PD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in the innate immune cell type monocytes and not in T cells that represent the adaptive arm of the immune system. Therefore, these loci represent excellent candidates as the first step in the cascade of molecular events that link genetic risk factors to the altered innate immune function that contributes to PD pathology. The principal goals of the proposed project are (1) to identify the component genes of networks perturbed by the PD susceptibility loci in myeloid cells (2) to understand their functional consequences on microglia behavior and (3) examine the role of these susceptibility loci on CNS microglia activation and gene expression.