The Role of Myeloid Cells in Parkinson's Disease

帕金森病 (PD) 是一种进行性神经退行性疾病，会导致衰老 影响运动和认知功能。尽管研究了五十多年，仍没有治愈方法 存在且治疗水平仍不令人满意。全基因组关联研究 （GWAS）已确定许多区域含有与 PD 相关的变异。下一个挑战 转化研究的目的是识别关联信号背后的因果变异， 受影响的基因、分子途径及其功能后果。因为遗传 变异可以通过对基因的影响来介导对高阶表型的影响 表达，将转录组学整合到疾病相关变异的研究中已经 已经被证明是一种有用的策略，并且确实已经显示出与疾病相关的位点 富集调节基因表达的变体。我们最近证明，遗传 影响骨髓细胞基因表达的变异是很大一部分的基础 与 PD 的遗传关联。我们还积累了令人信服的数据，表明许多基因 参与自噬-溶酶体途径和线粒体功能存在差异 与对照组相比，在 PD 病例的单核细胞和小胶质细胞中表达，并且在某些情况下， 受 PD 相关遗传变异的遗传调控。在这里，在目标 1 中，我们将生成批量和 250 个早期 PD 外周单核细胞的单细胞转录组和蛋白质组谱 （不用药，自症状出现起2年内），中晚期 PD 和来自特征明确的 PD 队列的年龄匹配对照。样本采集 转录组概况将纵向完成（在基线和 2 年内跟进） 年）。在目标 2 中，将表征来自以下来源的原代小胶质细胞的转录组： 对 PD 病例和年龄匹配的对照的尸检大脑的多个区域进行研究，并探索 PD易感性变异对转录组的影响。我们将进行 最先进的分析将整合多组学和临床数据集以生成 患者衍生的、数据驱动的、多尺度的疾病模型，能够生成 围绕特定于疾病状态和亚组的蛋白质相互作用的假设。在目标 3 中，我们将 对单核细胞和小胶质细胞进行功能表征，以研究基因的影响 表达、蛋白质丰度和网络连接变化可能对免疫功能产生影响 兴趣例如：1) 吞噬能力；；2) 溶酶体功能；；和 3) 线粒体活性。 该项目将通过以下方式产生巨大的总体影响：1）提供桥接 PD 遗传学的关键信息 单核细胞和小胶质细胞的分子机制，为未来的机制奠定基础 研究；（2）生成大规模、多组学数据集以及系统级别 对先天免疫细胞中的这些数据集进行分析，这是急需的资源。

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder of aging that affects both motor and cognitive function. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Genome-­wide association studies (GWAS) have identified many regions harboring variants associated with PD. The next challenge in translational research is to identify the causal variants underlying the association signals, the affected genes, molecular pathways and their functional consequences. Because genetic variants can mediate effects on higher-­order phenotypes through effects on gene expression, the integration of transcriptomics into the study of disease associated variants has already proven to be a useful strategy, and indeed disease associated loci have been shown to be enriched for variants regulating gene expression. We have recently shown that genetic variants that affect gene expression in myeloid cells underlie a substantial fraction of the genetic associations to PD. We have also accumulated compelling data suggesting that many genes involved in autophagy-­lysosomal pathways and mitochondrial function are differentially expressed in monocytes and in microglia of PD cases compared to controls and in some cases, are genetically regulated by PD-­associated genetic variants. Here, in aim 1, we will generate bulk and single cell transcriptome and proteome profiles from 250 peripheral monocytes of early-­stage PD (with no medication, within 2 years from the onset of the symptoms), mid-­ to late-­stage PD, and age-­matched controls from a well-­characterized PD cohort. The sample collection and transcriptome profiles will be done longitudinally (at baseline and follow up within 2 years). In aim 2, will characterize the transcriptome of primary microglia from multiple regions of autopsied brains of PD cases and age-­matched controls and explore the consequences on the transcriptome of PD susceptibility variants. We will conduct state-­of-­the-­art analyses that will integrate multi-­omic and clinical data sets to generate patient derived, data-­driven, multi-­scale models of disease, enabling the generation of hypotheses around protein interactions specific to disease states and subgroups. In aim 3, we will functionally characterize monocytes and microglia in order to investigate the effects that gene expression, protein abundance and network connectivity changes may have on immune functions of interest such as: 1) phagocytic capacity;; 2) lysosomal function;; and 3) mitochondrial activity. This project will have a large overall impact by: 1) providing key information bridging PD genetics to molecular mechanisms in monocytes and microglia, setting the stage for future mechanistic studies;; and (2) generating large-­scale, multi-­omic datasets, together with systems level analyses of these datasets in innate immune cells, which is an urgently needed resource.