Intersection of HSV-1 and microglial genetics in AD

AD 中 HSV-1 和小胶质细胞遗传学的交叉点

• 批准号: 10615906
• 负责人: Elizabeth M Bradshaw
• 金额: $ 80.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615906
• 关键词: Acceleration; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Agents; Autopsy; Bacteria; Blood Vessels; CD8-Positive T-Lymphocytes; Cells; Central Nervous System; Cerebrospinal Fluid; Childhood; Chlamydophila pneumoniae; Clinical; Clinical Trials; Clonal Expansion; Code; Communities; Computational Biology; DNA; Dementia; Disease; Epidemiology; Episodic memory; Etiology; Family member; Functional disorder; Gene Modified; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic study; Genotype; Goals; HHV-6A; Height; Herpes Labialis; Herpesviridae; Herpesvirus 1; Hippocampus; Human; Human Herpesvirus 4; Human Herpesvirus 7; Immune; Immune System Diseases; Immune response; Immune system; Immunology; Impaired cognition; Impairment; In Vitro; Individual; Infection; Infectious Agent; Innate Immune System; Late Onset Alzheimer Disease; Link; Measures; Mediating; Membrane Proteins; Memory; Microglia; Neurodegenerative Disorders; PLCG2 gene; Pathogenesis; Pathogenicity; Pathology; Phenotype; Play; Population; Porphyromonas gingivalis; Predisposition; Productivity; Proteins; Research Personnel; Risk Factors; Role; SPI1 gene; Senile Plaques; Signal Transduction; Suggestion; Susceptibility Gene; Symptoms; T cell infiltration; T-Cell Activation; T-Lymphocyte; TLR2 gene; Technology; Universities; Validation; Viral; Virus; Washington; Work; age related neurodegeneration; biobank; cell type; cohort; endophenotype; epidemiology study; fitness; genetic association; genetic risk factor; genetic variant; genome wide association study; human pathogen; immunoregulation; in vitro Model; monocyte; mouse model; novel; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; response; skills; tool; transcriptomics; virology

Project Summary Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genome-wide association studies have identified novel AD susceptibility loci. Interestingly the associated genes at several of these loci implicate the immune system in late-onset AD, specifically the innate immune system. Many recent lines of evidence suggest that the immune system plays a key role in AD initiation and progression, but the actual mechanistic dysfunction of the immune system in this neurodegenerative disease remains unknown. Genetic studies and pathology hint that the immune system’s ability to mount a productive response has been lost in AD with detrimental consequences. Post-mortem pathology of individuals with AD reveals an infiltration of T cells in the hippocampus, a region expected to be immune privileged, leading to speculation that AD might have an infectious component to its etiology or progression. In parallel, the pathogen hypothesis has garnered more support for a possible pathogenic etiology of AD. We propose to leverage our understanding of the immune system to determine if the immune response to the neuroinvasive pathogen human simplex virus (HSV)-1 is modulated by AD genetic associations, leading to increased risk for AD. We will take a comprehensive approach using cutting-edge tools to explore this hypothesis in AD. Combining genetics, human immunology, transcriptomics, virology, in vitro models, computational biology and epidemiology, we will dissect the interaction between HSV-1 infections and AD genetics. For this application, we propose a multifaceted approach using cutting-edge technology to: 1) identify the microglia response to HSV-1 infection based on each individual’s genetic background; 2) examine how these microglia function as antigen-presenting cells to T cells, a key cell type in resolving active infections; and 3) determine the interaction of HSV-1 and AD genetics in two well-establish cohorts and one anti-viral clinical trial in AD.

项目总结