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（由适用提供）：基因型对PD项目摘要/摘要中单核细胞/小胶质细胞表型和功能的影响。帕金森氏病（PD）是中枢神经系统（CNS）的退化性疾病，其特征是α-突触核蛋白的积累和聚集，其中nigra nigra死亡的多巴胺能神经元。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，我们假设先天细胞中的基因型差异，例如浸润巨噬细胞以及居民小胶质细胞参与PD的病理生理学，尤其是在这些多巴胺产生细胞的死亡中。我们对健康年轻人的数据的初步顺式CIS-EQTL分析已在髓样细胞功能中实施了8个PD易感基因，其表达相对于每个风险等位基因，在单核细胞中的表达变化，而不是代表免疫系统自适应部门的T细胞中的表达。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）确定PD易感性局部在髓样细胞中扰动的网络的组成基因（2），以了解其对单核细胞行为的功能后果，并且（3）检查这些易感性基因座对CNS小胶质细胞激活和基因表达的作用。