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: 10381305
• 负责人: Elizabeth M Bradshaw
• 金额: $ 77.71万
• 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/10381305
• 关键词: 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; CD8-Positive T-Lymphocytes; Cells; Cerebrospinal Fluid; Childhood; Chlamydophila pneumoniae; Clinical; Clinical Trials; 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; Herpes Labialis; Herpesviridae; Herpesvirus 1; Hippocampus (Brain); 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; Neuraxis; Neurodegenerative Disorders; PLCG2 gene; Pathogenesis; Pathogenicity; Pathology; Pharmaceutical Preparations; Phenotype; Play; Population; Porphyromonas gingivalis; Predisposition; Proteins; Research Personnel; Risk Factors; Role; SPI1 gene; Seeds; Senile Plaques; Signal Transduction; Suggestion; Susceptibility Gene; Symptoms; T-Cell Activation; T-Lymphocyte; TLR2 gene; Technology; Tumor-infiltrating immune cells; Universities; Validation; Virus; Washington; Work; age related neurodegeneration; apolipoprotein E-4; base; biobank; cell type; cohort; endophenotype; epidemiology study; fitness; genetic association; genetic risk factor; genetic variant; genome wide association study; human pathogen; in vitro Model; monocyte; mouse model; novel; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; response; skills; tool; transcriptomics; virology; 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; CD8-Positive T-Lymphocytes; Cells; Cerebrospinal Fluid; Childhood; Chlamydophila pneumoniae; Clinical; Clinical Trials; 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; Herpes Labialis; Herpesviridae; Herpesvirus 1; Hippocampus (Brain); 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; Neuraxis; Neurodegenerative Disorders; PLCG2 gene; Pathogenesis; Pathogenicity; Pathology; Pharmaceutical Preparations; Phenotype; Play; Population; Porphyromonas gingivalis; Predisposition; Proteins; Research Personnel; Risk Factors; Role; SPI1 gene; Seeds; Senile Plaques; Signal Transduction; Suggestion; Susceptibility Gene; Symptoms; T-Cell Activation; T-Lymphocyte; TLR2 gene; Technology; Tumor-infiltrating immune cells; Universities; Validation; Virus; Washington; Work; age related neurodegeneration; apolipoprotein E-4; base; biobank; cell type; cohort; endophenotype; epidemiology study; fitness; genetic association; genetic risk factor; genetic variant; genome wide association study; human pathogen; 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.

项目摘要 阿尔茨海默氏病（AD）是一种与年龄有关的神经退行性疾病，其特征是进行性认知 衰落和痴呆。全基因组关联研究已经确定了新型的AD敏感性局部。有趣的是 其中几个基因座的相关基因暗示了晚期AD中的免疫系统，特别是 先天免疫系统。最近的许多证据表明，免疫系统在AD中起关键作用 启动和进展，但是免疫系统的实际机械功能障碍 神经退行性疾病仍然未知。遗传研究和病理学暗示了免疫系统 在AD中丢失了无法实现产品响应的能力，并带来了不利的后果。验尸 AD患者的病理学揭示了海马中T细胞的浸润，该区域预计为 免疫特权，导致猜测AD可能具有感染性的病因或病因或 进展。同时，病原体假设获得了对可能的致病性病因的更多支持 广告。我们建议利用对免疫系统的理解来确定免疫反应是否 对于神经侵染致病的人类单纯形病毒（HSV）-1，由AD遗传关联调节，领先 增加AD风险。我们将使用尖端工具采用全面的方法来探索这一点 AD中的假设。结合遗传学，人类免疫学，转录组学，病毒学，体外模型， 计算生物学和流行病学，我们将剖析HSV-1感染与AD之间的相互作用 遗传学。对于此应用程序，我们建议使用尖端技术的多方面方法来：1） 基于每个人的遗传背景对HSV-1感染的小胶质细胞反应； 2）检查如何 小胶质细胞充当T细胞的抗原呈递细胞，T细胞是解决主动感染的钥匙细胞类型； 3） 确定两个良好的队列和一项抗病毒临床试验中HSV-1和AD遗传学的相互作用 在广告中。