The Role of Myeloid Cells in Parkinson's Disease

帕金森氏病（PD）是一种进行性的神经退行性疾病， 影响运动和认知功能尽管经过了50多年的研究， 然而，治疗标准仍然不令人满意。全基因组关联研究 （GWAS）已经鉴定了许多携带与PD相关的变体的区域。下一个挑战 在翻译研究中，是识别关联信号背后的因果变体， 受影响的基因、分子通路及其功能后果。因为遗传 变异体可以通过对基因的影响来介导对更高级表型的影响。 表达，将转录组学整合到疾病相关变体的研究中， 已经被证明是一种有用的策略，事实上，已经显示出疾病相关的基因座， 以富集调节基因表达的变体。我们最近发现， 影响骨髓细胞中基因表达的变异体是骨髓细胞中大部分基因表达的基础。 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 参与自噬的溶酶体途径和线粒体功能是不同的 与对照相比，PD病例的单核细胞和小胶质细胞中表达，在某些情况下， 由PD-L1相关的遗传变异体进行遗传调节。在这里，在目标1中，我们将生成批量， 250例帕金森病早期外周血单核细胞单细胞转录组和蛋白质组研究 (with症状出现后2年内未服用药物），中期至晚期 PD和年龄匹配的对照，来自一个充分表征的PD队列。样本收集 和转录组谱将纵向完成（在基线和随访2 年）。在目标2中，将描述来自于人的原发性小胶质细胞的转录组， 对帕金森病患者和年龄匹配的对照者的多个脑区进行尸检， 对PD易感性变体的转录组的影响。我们会进行 最先进的分析，将整合多个药物组学和临床数据集， 患者衍生的、数据驱动的、多尺度的疾病模型， 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 为了研究基因对单核细胞和小胶质细胞的影响， 表达、蛋白质丰度和网络连接性的变化可能对免疫功能产生影响， 例如：1）吞噬能力; 2）溶酶体功能; 3）线粒体活性。 该项目将产生巨大的整体影响：1）提供关键信息桥接PD遗传学 单核细胞和小胶质细胞的分子机制，为未来的机制奠定了基础。 研究;（2）生成大规模，多学科数据集，以及系统级 分析先天免疫细胞中的这些数据集，这是一个迫切需要的资源。

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.