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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。而在神经炎性淀粉样变附近观察到活化的小胶质细胞。阿尔茨海默病(AD)中的斑块，目前还没有大规模的小胶质细胞激活评估。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--特别是处于形态定义的激活状态的小胶质细胞的比例--增加对阿尔茨海默病的易感性，所以我们可以开发更有针对性的基于免疫的疗法来防止认知衰退和发展为痴呆症。我们的目标是改进小胶质细胞激活的遗传结构，以寻找影响激活的小胶质细胞比例的新的基因座，并了解其功能阿尔茨海默病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的基因突变体影响小胶质细胞的激活和AD的易感性。我们将通过以下方式验证这一假设：全基因组分析和确定基因变异和小胶质细胞激活之间的关联。小胶质细胞将使用PET成像技术测量人体尸检组织(体外)、活体人脑(体内)的活性，单核细胞来源的小胶质细胞样细胞(原位和体外)。我们的理论基础是绘制基因图谱推动激活的小胶质细胞比例的体系结构将在开发第一代这一特征的多基因模型，并确定激活的小胶质细胞的比例是否捕捉到一个原因通向AD的级联过程中的元素。我们的具体目标是1)验证和发现影响老年和阿尔茨海默病患者人小胶质细胞激活(激活的小胶质细胞比例)的死后测量疾病，2)活体验证GWAS并使用TSPO PET成像评估临床相关性检测小胶质细胞的活化，3)原位组织学和体外功能特征验证人类小胶质细胞系统中的变种。对于第一个目标，我们将执行GWA并测量其比例从1600人的尸检脑组织中发现激活的小胶质细胞，然后将我们的发现复制到来自三个不同机构的独立的、多样化的样本集。在第二个目标中，我们将执行GWA 以及TSPO PET成像，使用最先进的放射性配基11C-ER176，在200名老年人的前瞻性队列中人类受试者(认知正常、轻度认知障碍和阿尔茨海默病的比例相等) 确定与阿尔茨海默病相关的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 AIMS 1和2中发现的变异体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和人类细胞小胶质细胞的测量激活以创建对小胶质细胞反应的遗传结构的多模式调查。建议数这项研究意义重大，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，将为确定药物潜在治疗靶点的优先顺序提供关键见解开发和创造用于指导临床试验设计的新的结果指标。