Influence of genotype on monocyte and microglia phenotype and function in Parkinson's disease (PD)

基因型对帕金森病（PD）单核细胞和小胶质细胞表型和功能的影响

• 批准号: 8928814
• 负责人: Elizabeth M Bradshaw
• 金额: $ 46.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928814
• 关键词: Aging; Autopsy; Behavior; Biochemical; CD14 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Central Nervous System Degenerative Diseases; Cessation of life; Complex; DNA; Data; Data Analyses; Derivation procedure; Diagnosis; Disease; Disease Progression; Disease susceptibility; Dopamine; Environmental Risk Factor; Event; Flow Cytometry; Functional disorder; Gene Components; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genotype; Goals; Health; Hereditary Disease; ITGAM gene; Immune; Immune system; Individual; Inflammation; Inflammatory; LRRK2 gene; Lead; Lewy Bodies; Link; Maps; Microglia; Molecular; Molecular Profiling; Movement Disorders; Myelogenous; Myeloid Cells; Nerve Degeneration; Neuraxis; Neurons; Outcome; Parkinson Disease; Pathology; Pathway interactions; Patients; Peripheral; Phagocytosis; Phenotype; Play; Predisposition; Prevention; Prospective Studies; Protein Isoforms; Proteins; Public Health; RNA Sequences; RNA Splicing; Regulation; Relative (related person); Role; Single Nucleotide Polymorphism; Substantia nigra structure; Susceptibility Gene; Systems Biology; T-Lymphocyte; Validation; Variant; Western Blotting; abstracting; alpha synuclein; arm; base; brain tissue; cell type; clinical phenotype; cohort; disorder risk; dopaminergic neuron; genetic risk factor; genetic variant; genome wide association study; genome-wide; innate immune function; macrophage; monocyte; neuron loss; novel; protein expression; public health priorities; risk variant; small hairpin RNA; therapeutic target; transcriptomics; young adult

DESCRIPTION (provided by applicant): Influence of genotype on monocyte/microglia phenotype and function in PD Project Summary/Abstract. Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) characterized by the accumulation and aggregation of α-synuclein in which the dopaminergic neurons of the substantia nigra die. The innate immune system is thought to play a role in the demise of these neurons. Therefore, we hypothesized that genotypic differences in innate cells, such as infiltrating macrophages as well as resident microglia are involved in the pathophysiology of PD and, particularly, in the death of these dopamine producing cells. Our preliminary cis-eQTL analyses of data from healthy young individuals have implicated 8 PD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in monocytes and not in T cells that represent the adaptive arm of the immune system. Therefore, these loci represent excellent candidates as the first step in the cascade of molecular events that link genetic risk factors to the altered innate immune function that contributes to PD pathology. The principal goals of the proposed project are (1) to identify the component genes of networks perturbed by the PD susceptibility loci in myeloid cells (2) to understand their functional consequences on monocyte behavior and (3) examine the role of these susceptibility loci on CNS microglia activation and gene expression.

描述（由申请方提供）：PD项目总结/摘要中基因型对单核细胞/小胶质细胞表型和功能的影响。帕金森病（Parkinson's disease，PD）是一种以α-突触核蛋白聚集和聚集为特征的中枢神经系统退行性疾病，其中黑质多巴胺能神经元死亡。先天免疫系统被认为在这些神经元的死亡中起作用。因此，我们假设先天细胞的基因型差异，如浸润性巨噬细胞以及常驻小胶质细胞参与PD的病理生理学，特别是这些多巴胺产生细胞的死亡。我们对来自健康年轻个体的数据进行的初步顺式eQTL分析表明，骨髓细胞功能中有8个PD易感基因，其表达相对于每个风险等位基因在单核细胞中而不是在代表免疫系统适应性臂的T细胞中发生改变。因此，这些基因座代表了极好的候选者，作为将遗传风险因素与导致PD病理学改变的先天免疫功能联系起来的分子事件级联中的第一步。拟议项目的主要目标是（1）识别骨髓细胞中受PD易感性基因座干扰的网络的组成基因（2）了解其对单核细胞行为的功能后果和（3）检查这些易感性基因座对中枢神经系统小胶质细胞的作用激活和基因表达。