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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.

帕金森病（PD）是一种进行性神经退行性疾病