Influence of genotype on monocyte and microglia phenotype and function in Parkinson's disease (PD)

描述（由申请方提供）：PD项目总结/摘要中基因型对单核细胞/小胶质细胞表型和功能的影响。帕金森病（Parkinson's disease，PD）是一种以α-突触核蛋白聚集和聚集为特征的中枢神经系统退行性疾病，其中黑质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，我们假设先天细胞的基因型差异，如浸润性巨噬细胞以及常驻小胶质细胞参与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，骨髓细胞功能中有8个PD易感基因，其表达相对于每个风险等位基因在单核细胞中而不是在代表免疫系统适应性臂的T细胞中发生改变。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）确定髓系细胞中PD易感基因座干扰网络的组成基因;（2）了解其对单核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): Influence of genotype on monocyte/microglia phenotype and function in PD Project Summary/Abstract. Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) characterized by the accumulation and aggregation of α-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 innate cells, such as infiltrating macrophages as well as resident 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 8 PD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in 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 monocyte behavior and (3) examine the role of these susceptibility loci on CNS microglia activation and gene expression.