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（由适用提供）：帕金森氏病（PD）是中枢神经系统（CNS）的退化性疾病，其特征是a核蛋白的累积和聚集，在该核蛋白中，尼格拉死模的多巴胺能神经元。先天免疫系统被认为在这些神经元的消亡中发挥作用。因此，我们假设小胶质细胞的基因型差异与PD的病理生物生物生物学有关，尤其是我们对健康年轻人的数据的初步CIS-EQTL分析，在每个风险中，与每个风险相对的表达，相对于天生的免疫细胞的表达，都在现有的，是在髓样细胞功能中实现了11个PD易感基因 键入单核细胞，而不是代表免疫系统自适应臂的T细胞中。因此，这些地方代表了出色的候选者，这是一系列分子事件的第一步，将遗传风险因素与改变的先天免疫功能联系起来，这有助于PD病理。拟议项目的主要目标是（1）识别Pd易感性局部在髓样细胞中扰动的网络的组成基因（2），以了解其对小胶质细胞行为的功能后果，并且（3）检查这些易感性位置对CNS小胶质细胞激活和基因表达的作用。