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Discovery and validation of genetic variants affecting microglial activation in Alzheimer's disease

影响阿尔茨海默病小胶质细胞激活的遗传变异的发现和验证

基本信息

批准号：
10101207
负责人：
PHILIP L DE JAGER
金额：
$ 621.32万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10101207
关键词：
Adult Affect African American Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Architecture Automobile Driving Autopsy Binding Biological Biological Markers Brain Brain Diseases Cell physiology Cells Chromosome 1 Chromosome Mapping Clinical Clinical Trials Clinical Trials Design Clinical assessments Cognitive Data Data Set Dementia Development Disease Disease susceptibility Elements Future Gene Proteins Generations Genes Genetic Genetic study Goals Histologic Human Human Biology Image Immune Immunotherapy Impaired cognition In Situ In Vitro Individual Institution Investigation Joints Knowledge Ligands Maps Measures Memory Mental disorders Microglia Mission Modeling Morphology Myelogenous Neurodegenerative Disorders New York Onset of illness Outcome Measure PLCG2 gene Participant Pathology Phagocytosis Positron-Emission Tomography Predisposition Prospective cohort Proteins Public Health Randomized Regulation Research Role Sampling Senile Plaques Societies Structure Susceptibility Gene Synaptosomes System TREM2 gene TYROBP gene Testing Tissues Translating Translations Validation Variant base brain cell brain health brain tissue causal model clinically relevant cohort drug development gene discovery genetic architecture genetic variant genome wide association study genome-wide genome-wide analysis genomic locus human subject immune function in vivo innovation insight migration mild cognitive impairment monocyte multimodality nervous system disorder neuroinflammation neuropsychiatric disorder novel prevent prospective protein expression radioligand religious order study response tau Proteins tau aggregation therapeutic target trait transcriptome

项目摘要

Project Summary/Abstract. While activated microglia have been observed in the vicinity of neuritic amyloid plaques in Alzheimer's disease (AD), there have been no large-scale assessments of microglial activation in aging and neurodegenerative disease. Our long-term goal is to understand the genetic underpinning of microglial responses—particularly the proportion of microglia in a morphologically-defined state of activation—that increase susceptibility to AD, so we can develop more targeted forms of immune-based therapies to prevent cognitive decline and progression to dementia. Our objective is to refine the genetic architecture of microglial activation to identify novel loci that influence the proportion of activated microglia, and to understand the functional consequences of variants driving microglial activation in AD. Our central hypothesis is that identifiable gene variants influence microglial activation and susceptibility to AD. We will test this hypothesis by conducting genome-wide analysis and identifying associations between gene variants and microglial activation. Microglial activation will be measured in human autopsy tissue (ex vivo), living human brain using PET imaging (in vivo), and in monocyte-derived microglia-like cells (in situ and in vitro). Our rationale is that mapping the genetic architecture that drives the proportion of activated microglia will be important in developing a first generation of polygenic models for this trait and determine whether the proportion of activated microglia captures a causal element of the cascade leading to AD. Our specific aims are 1) Validation and discovery of loci influencing a postmortem measure of human microglial activation (proportion of activated microglia) in aging and Alzheimer's disease, 2) In vivo validation of GWAS and assessment of clinical relevance using TSPO PET imaging to measure microglial activation, and 3) In situ histological and in vitro functional characterization of validated variants in a human microglia-like system. For the first aim, we will perform GWAS and measure the proportion of activated microglia in autopsy brain tissue from 1,600 individuals, and then replicate our findings in an independent, diverse set of samples from three separate institutions. In the second aim, we will perform GWAS and TSPO PET imaging, using the state-of-the-art radioligand 11C-ER176, in a prospective cohort of 200 older human subjects (equal proportions of cognitively normal, mild cognitive impairment, and Alzheimer's disease) to identify gene variants associated with AD-related microglial activation. In the third aim, we will assess how gene variants identified in Aims 1 and 2 influence cellular function and protein expression in monocyte-derived microglia-like cells. Our innovative approach combines autopsy, PET, and human cell measures of microglial activation to create a multimodal investigation into the genetic architecture of microglial responses. The proposed research is significant, as mapping the variants that regulate microglial activation, and determining their functional consequences, will provide key insights in prioritizing potential therapeutic targets for drug development and in creating novel outcome measures with which to guide clinical trial design.

项目摘要/摘要。虽然在神经炎淀粉样蛋白附近观察到活化的小胶质细胞阿尔茨海默病（AD）斑块中，尚未对小胶质细胞激活进行大规模评估衰老和神经退行性疾病。我们的长期目标是了解小胶质细胞的遗传基础反应——特别是处于形态学定义的激活状态的小胶质细胞的比例——增加 AD 的易感性，因此我们可以开发更有针对性的免疫疗法来预防认知障碍衰退并进展为痴呆。我们的目标是完善小胶质细胞激活的遗传结构识别影响活化小胶质细胞比例的新位点，并了解其功能 AD 中驱动小胶质细胞激活的变异的后果。我们的中心假设是可识别基因变异会影响小胶质细胞的激活和 AD 的易感性。我们将通过进行测试这个假设全基因组分析并识别基因变异与小胶质细胞激活之间的关联。小胶质细胞将使用 PET 成像在人体尸检组织（离体）、活人大脑（体内）中测量激活，以及单核细胞衍生的小胶质细胞样细胞（原位和体外）。我们的基本原理是绘制遗传图谱驱动激活小胶质细胞比例的结构对于开发第一代小胶质细胞非常重要该性状的多基因模型，并确定激活的小胶质细胞的比例是否捕获了因果关系导致 AD 的级联元素。我们的具体目标是 1) 验证和发现影响基因座衰老和阿尔茨海默病中人类小胶质细胞活化（活化小胶质细胞的比例）的死后测量疾病，2) 使用 TSPO PET 成像对 GWAS 进行体内验证并评估临床相关性测量小胶质细胞的激活，以及 3) 经过验证的原位组织学和体外功能表征人类小胶质细胞样系统的变异。对于第一个目标，我们将进行 GWAS 并测量比例对 1,600 名个体尸检脑组织中激活的小胶质细胞进行研究，然后在一个来自三个独立机构的独立、多样化的样本集。第二个目标，我们将进行GWAS 和 TSPO PET 成像，使用最先进的放射性配体 11C-ER176，在 200 名老年人的前瞻性队列中进行人类受试者（认知正常、轻度认知障碍和阿尔茨海默病的比例相同）识别与 AD 相关小胶质细胞激活相关的基因变异。在第三个目标中，我们将评估基因如何目标 1 和 2 中鉴定的变异影响单核细胞来源的细胞功能和蛋白质表达小胶质细胞样细胞。我们的创新方法结合了尸检、PET 和小胶质细胞的人体细胞测量激活以对小胶质细胞反应的遗传结构进行多模式研究。拟议的研究意义重大，因为绘制了调节小胶质细胞激活的变异，并确定了它们的功能后果，将为优先考虑药物潜在治疗靶点提供重要见解开发并创建指导临床试验设计的新结果衡量标准。