Uncovering the Role of the MS4A Gene Family in Alzheimer's Disease

揭示 MS4A 基因家族在阿尔茨海默病中的作用

基本信息

批准号：
10751885
负责人：
Alexandra Munch
金额：
$ 4.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2026-08-13
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751885
关键词：
Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Amyloid deposition Animal Model Binding Binding Proteins Binding Sites Biological Biological Assay Biological Markers Biological Process Brain CCCTC-binding factor Cell Culture Techniques Cell Line Cell physiology Cells Central Nervous System Chromosome 11 Clustered Regularly Interspaced Short Palindromic Repeats Cognition Containment Data Set Disease Disease Progression Disease susceptibility Drug Targeting Enhancers Etiology Foundations Future Gene Cluster Gene Expression Gene Family Genes Genetic Genetic Diseases Genomics Genotype Human Human Genetics Immune Immune signaling Immunologic Receptors Impaired cognition In Vitro Injections Innate Immune System Integral Membrane Protein Knock-out Light Macrophage Maps Measures Mediating Membrane Memory Loss Memory impairment Methods Microglia Morphology Mus Myelogenous Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Nucleotides Outcome Pathologic Phagocytosis Phenotype Play Production Proteins Public Health Reactive Oxygen Species Research Research Personnel Risk Role Senile Plaques Signal Transduction Single Nucleotide Polymorphism Statistical Study TREM2 gene Techniques Testing Training Translating Transplantation Validation Variant Work Xenograft Model Xenograft procedure amyloid pathology career causal variant cell type chromatin remodeling cytokine disorder risk drug development drug discovery effective therapy epigenomics executive function experimental study functional genomics gene function genetic variant genome wide association study humanized mouse in vitro Model in vivo induced pluripotent stem cell innovation loss of function member mouse model new therapeutic target novel precursor cell protective allele response risk variant selective expression single nucleus RNA-sequencing skills stem cell model stem cells targeted treatment tau-1 therapeutically effective transcriptomics

Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Amyloid deposition Animal Model Binding Binding Proteins Binding Sites Biological Biological Assay Biological Markers Biological Process Brain CCCTC-binding factor Cell Culture Techniques Cell Line Cell physiology Cells Central Nervous System Chromosome 11 Clustered Regularly Interspaced Short Palindromic Repeats Cognition Containment Data Set Disease Disease Progression Disease susceptibility Drug Targeting Enhancers Etiology Foundations Future Gene Cluster Gene Expression Gene Family Genes Genetic Genetic Diseases Genomics Genotype Human Human Genetics Immune Immune signaling Immunologic Receptors Impaired cognition In Vitro Injections Innate Immune System Integral Membrane Protein Knock-out Light Macrophage Maps Measures Mediating Membrane Memory Loss Memory impairment Methods Microglia Morphology Mus Myelogenous Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Nucleotides Outcome Pathologic Phagocytosis Phenotype Play Production Proteins Public Health Reactive Oxygen Species Research Research Personnel Risk Role Senile Plaques Signal Transduction Single Nucleotide Polymorphism Statistical Study TREM2 gene Techniques Testing Training Translating Transplantation Validation Variant Work Xenograft Model Xenograft procedure amyloid pathology career causal variant cell type chromatin remodeling cytokine disorder risk drug development drug discovery effective therapy epigenomics executive function experimental study functional genomics gene function genetic variant genome wide association study humanized mouse in vitro Model in vivo induced pluripotent stem cell innovation loss of function member mouse model new therapeutic target novel precursor cell protective allele response risk variant selective expression single nucleus RNA-sequencing skills stem cell model stem cells targeted treatment tau-1 therapeutically effective transcriptomics

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项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a grave neurodegenerative disorder characterized by unrelenting memory loss and deficits in executive function with no effective treatment. Accumulating evidence from genome wide association studies (GWAS) posit that the brain’s innate immune system plays a central role in AD etiology. As the central nervous system’s resident immune cells, microglia have thus emerged as attractive cells to target therapeutically. Such drug targets may lie within the MS4A locus, a region associated with protection from AD, later age-at- onset, and increased levels of sTREM2, a biomarker of microglial activity. This region contains multiple genes within the membrane-spanning 4-domain subfamily A (MS4A) gene cluster, which together encode structurally related transmembrane proteins largely expressed by immune cells whose exact functions are not yet understood. Our work nominated a candidate causal variant within this locus, rs636317, which disrupts an anchor binding site for the chromatin remodeling protein CTCF and is associated with increased expression of MS4A4A and MS4A6A in myeloid cells. This proposal aims to directly test the hypothesis that by modulating MS4A4A and MS4A6A expression via differential CTCF binding, variant rs636317 alters microglial cell function in the context of disease. In AIM 1, I will determine the functional impact of MS4A genes in vitro using CRISPR-edited human induced pluripotent stem cell (iPSC)-derived microglia (iMGL). Given known interactions between MS4A proteins and other immune receptors such as TREM2 and CLEC7A, I will perform targeted functional assays related to immune signaling in iMGLs from two iPSC models: MS4A4A/MS4A6A knockout lines and isogenic lines homozygous for the protective or risk alleles of the candidate causal variant. In AIM 2, I will employ a novel xenotransplantation model involving direct injection of human microglia precursor cells into the mouse brain to evaluate the effect of these genes on cell function in vivo and in the context of disease using 5xFAD chimeric mice. I hypothesize that knocking out MS4A4A and MS4A6A in human microglia promotes protective microglial responses, ameliorating plaque containment and subsequent cognitive decline. Elucidating the function of this gene family and the specific role it plays in AD progression has the potential to greatly impact public health. The proposed research and rigorous training plan outlined here will equip me with the skills needed for a successful future career in neurodegeneration leading an independent research team.

项目摘要阿尔茨海默氏病（AD）是一种严重的神经退行性疾病，其特征是记忆丧失和执行功能的缺陷无效治疗。基因组广泛关联的积累证据研究（GWAS）认为大脑的先天免疫系统在AD病因中起着核心作用。作为中央神经系统的居民免疫细胞，小胶质细胞已成为有吸引力的细胞，可以治疗。这种药物靶标可能位于MS4A基因座，该区域与AD保护相关的区域，以后的年龄发作和streem2的水平增加，这是小胶质活性的生物标志物。该区域包含多个基因在膜跨膜4域亚菌A（MS4A）基因簇中，该基因共同在结构上编码相关的跨膜蛋白主要由免疫细胞表达，其确切功能尚未理解齿。我们的作品提名了该基因座的候选因果变体RS636317，该变体破坏了锚点染色质重塑蛋白CTCF的结合位点，与MS4A4A的表达增加有关和髓样细胞中的MS4A6A。该建议旨在直接检验以下假设，即通过调节MS4A4A和 MS4A6A通过微分CTCF结合表达，变体RS636317在上下文中改变小胶质细胞功能疾病。在AIM 1中，我将使用CRISPR编辑的人类确定MS4A基因在体外的功能影响诱导多能干细胞（IPSC）衍生的小胶质细胞（IMGL）。给定MS4A蛋白之间的已知相互作用以及其他免疫感受器，例如Trem2和Clec7a，我将执行与来自两种IPSC模型的IMGL中的免疫信号传导：MS4A4A/MS4A6A敲除线和同源线候选因果变体的受保护或风险等位基因的纯合子。在AIM 2中，我将采用小说异种移植模型涉及直接注入人类小胶质细胞细胞到小鼠脑中评估这些基因在体内和疾病中使用5XFAD嵌合的影响老鼠。我假设在人类小胶质细胞中淘汰MS4A4A和MS4A6A会促进保护性小胶质细胞反应，改善斑块遏制以及随后的认知能力下降。阐明此功能基因家族及其在广告发展中扮演的具体作用有可能极大地影响公共卫生。这拟议的研究和严格的培训计划将为我提供成功的技能神经变性领域的未来职业领导一个独立的研究团队。