The Role of Myeloid Cells in Parkinson's Disease

骨髓细胞在帕金森病中的作用

基本信息

批准号：
10377952
负责人：
Towfique Raj
金额：
$ 69.72万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377952
关键词：
Affect Age Aging Autophagocytosis Autopsy Brain CD14 gene Cell physiology Cells Clinical Data Data Data Set Disease Disease model Foundations Functional disorder Future Gene Expression Gene Proteins Generations Genes Genetic Diseases Genetic Polymorphism Genetic Transcription Genetic Variation Genotype Goals Heterogeneity Human Immune Immune system Impairment Individual Lead Link Measures Mediating Microglia Mitochondria Molecular Motor Multiomic Data Myelogenous Myeloid Cells Neurodegenerative Disorders Parkinson Disease Pathogenesis Pathway interactions Patients Peripheral Phagocytes Pharmaceutical Preparations Phenotype Proteins Proteome Quantitative Trait Loci Research Resources Risk Role Signal Transduction Subgroup Susceptibility Gene Symptoms System T-Lymphocyte Technology Testing Translational Research Variant Visit Work arm case control causal variant cognitive function cohort differential expression disorder risk follow-up functional genomics genetic association genetic risk factor genetic variant genome wide association study immune function innate immune function interest macrophage mitochondrial dysfunction monocyte multi-scale modeling multiple omics new therapeutic target novel diagnostics novel therapeutic intervention rare variant risk variant sample collection standard care therapeutic development transcriptome transcriptomics validation studies

项目摘要

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.

帕金森氏病（PD）是一种进步的，神经退行性的衰老疾病，影响运动和认知功能。尽管进行了五十年的研究，但没有治疗存在，治疗标准仍然不令人满意。全基因组关联研究（GWAS）已经确定了许多具有与PD相关的变体的区域。下一个挑战在翻译研究中是确定关联信号的基础的因果变异，受影响的基因，分子途径及其功能后果。因为遗传变体可以通过对基因的影响介导对高阶表型的影响表达，转录组学与疾病相关变异的研究的整合具有已经被证明是一种有用的策略，并且确实显示了与疾病相关的局部策略要富含变体调控基因表达。我们最近表明了通用影响基因表达的髓样细胞中的变异，这是大部分的大部分与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 - 溶糖途径和线粒体功能的参与差异与对照组相比，在单核细胞和PD病例的小胶质细胞中表达，在某些情况下是受PD相关遗传变异的遗传调节。在AIM 1中，我们将产生批量，来自250个早期PD的250个周围单核细胞的单细胞转录组和蛋白质组轮廓（在症状发作后2年内没有药物治疗），中期至后期 PD和年龄匹配的对照，来自特征良好的PD队列。样本收集和转录组轮廓将纵向完成（基线时，然后在2个之内进行跟进年）。在AIM 2中，将表征来自原代小胶质细胞的转录组 PD病例和年龄匹配的对照的多个区域的大脑的多个区域对PD易感性变体的转录组的后果。我们将进行最先进的分析将整合多摩管和临床数据集以生成患者得出的，数据驱动的，多尺度的疾病模型，使能够产生围绕特定于疾病状态和亚组的蛋白质相互作用的假设。在AIM 3中，我们将在功能上表征单核细胞和小胶质细胞，以研究基因的影响表达，蛋白质抽象和网络连通性变化可能会在免疫功能上具有兴趣，例如：1）吞噬能力； 2）溶酶体功能;; 3）线粒体活性。该项目将产生很大的总体影响：1）提供关键信息桥接PD遗传学到单核细胞和小胶质细胞中的分子机制，为将来的机械奠定了基础研究；（2）生成大规模的多摩变数据集，以及系统级别对天生免疫核管中这些数据集的分析，这是迫切需要的资源。