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， 会影响运动和认知功能。尽管进行了50多年的研究，但没有治愈方法 仍然存在，治疗标准仍然不能令人满意。全基因组关联研究 (Gwas)发现了许多与帕金森病相关的变异体。下一个挑战 在翻译研究中的目的是识别关联信号背后的因果变体， 受影响的基因、分子途径及其功能后果。因为基因 变异体可以通过对基因的影响来调节对高阶表型的影响 表达，将转录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，而且确实已经显示了与疾病相关的基因座 以丰富调控基因表达的变异体。我们最近已经证明了基因 影响髓系细胞基因表达的变异在很大程度上是 帕金森病的遗传关联。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不同 在PD患者的单核细胞和小胶质细胞中的表达与对照组相比，在某些情况下是 受帕金森病相关基因变异的基因调控。在这里，在目标1中，我们将生成批量和 250例早期帕金森病患者外周血单核细胞转录组和蛋白质组分析 (不服药，自症状出现起2年内)，中晚期 帕金森病，以及年龄匹配的对照组，来自特征良好的帕金森病队列。样本收集 转录组分析将纵向进行(在基线和2个月内进行跟踪 年)。在目标2中，将描述来自于 对帕金森病患者和年龄匹配的对照组的多个脑区进行解剖，并探讨 对帕金森病易感变异体转录组的影响。我们将进行 最先进的分析，将整合多组数据和临床数据集以生成 患者派生的、数据驱动的多尺度疾病模型，使 围绕特定于疾病状态和亚群的蛋白质相互作用的假说。在《目标3》中，我们将 对单核细胞和小胶质细胞进行功能鉴定，以研究该基因的作用 表达、蛋白丰度和网络连通性变化对免疫功能的影响 兴趣包括：1)吞噬能力；2);；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整体影响：1)提供连接帕金森病遗传学的关键信息 单核细胞和小胶质细胞的分子机制，为未来的机制奠定了基础 研究；;和(2)生成大规模、多组数据集，以及系统级 对先天免疫细胞中这些数据集的分析，这是一种迫切需要的资源。

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.