Influence of genotype on microglia phenotype and function in PD

帕金森病中基因型对小胶质细胞表型和功能的影响

• 批准号: 8965189
• 负责人: Elizabeth M Bradshaw
• 金额: $ 36.73万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965189
• 关键词: Aging; Autopsy; Behavior; Biochemical; Brain; CD14 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Central Nervous System Degenerative Diseases; Cessation of life; Complex; DNA; Data; Data Analyses; Data Set; Derivation procedure; Diagnosis; Disease; Disease Progression; Disease susceptibility; Dopamine; Environmental Risk Factor; Event; Flow Cytometry; Functional disorder; Funding; Gene Components; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genotype; Goals; Hereditary Disease; Homeostasis; Human; 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; Phagocytosis; Phase; 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; alpha synuclein; arm; base; brain tissue; cell type; clinical phenotype; cohort; differential expression; disorder risk; dopaminergic neuron; genetic risk factor; genetic variant; genome wide association study; genome-wide; in vitro Model; innate immune function; macrophage; monocyte; neuron loss; novel; protein expression; public health priorities; public health relevance; risk variant; sample collection; small hairpin RNA; synuclein; therapeutic target; transcriptome sequencing; transcriptomics

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) characterized by the accumulation and aggregation of a-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 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 11 PD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in the innate immune cell type 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 microglia behavior and (3) examine the role of these susceptibility loci on CNS microglia activation and gene expression.

 描述(申请人提供)：帕金森病(PD)是一种中枢神经系统(CNS)的退行性疾病，特征是α-突触核蛋白的积聚和聚集，其中黑质的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发挥了作用。因此，我们假设小胶质细胞中的基因差异与帕金森病的病理生理学有关，特别是与这些产生多巴胺的细胞的死亡有关。我们对健康年轻人数据的初步cis-eQTL分析表明，11个PD易感基因与髓系细胞功能有关，它们的表达相对于每个危险等位基因在先天免疫细胞中发生了变化。 类型的单核细胞，而不是代表免疫系统适应性手臂的T细胞。因此，这些基因座代表了极好的候选基因，作为分子事件级联反应的第一步，这些分子事件将遗传风险因素与导致PD病理的先天免疫功能改变联系在一起。该项目的主要目标是(1)确定髓系细胞中受PD易感基因干扰的网络的组成基因(2)了解它们对小胶质细胞行为的功能影响和(3)检测这些易感基因对中枢神经系统小胶质细胞激活和基因表达的作用。