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Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia

使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因

基本信息

批准号：
10615602
负责人：
Todd Jonathan Cohen
金额：
$ 72.23万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615602
关键词：
3-Dimensional Acceleration Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Base Pairing Binding Biological Assay Cell Culture Techniques Chromatin Chromatin Loop Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Data Set Diagnosis Disease Distal Enhancers Event Foundations Genes Genetic Genetic Transcription Genomics Goals Histone Acetylation Human Link Maps Mediating Microglia Modeling Molecular Nerve Degeneration Nucleic Acid Regulatory Sequences Pathogenicity Play Protocols documentation Regulatory Element Reporter Research Resolution Rest Risk Role Senile Plaques Single Nucleotide Polymorphism Speed Stimulus TREM2 gene Techniques Testing Transcriptional Regulation Untranslated RNA Variant Work apolipoprotein E-4 biological systems brain cell brain tissue causal variant cell type drug development experimental study genetic variant genome editing genome wide association study genomic locus high throughput technology induced pluripotent stem cell novel protective allele response risk variant tool tool development transcription factor transcription regulatory network

项目摘要

Project Abstract Treatment options for Alzheimer’s disease have been elusive, in large part because the molecular mecha- nisms underlying AD remain unclear. Genome-wide association studies (GWAS) have uncovered genomic loci associated with increased risk of AD; however, the exact causal variants within these loci and the genes they affect have been difficult to determine. While many lines of evidence suggest that these variants alter transcriptional regulatory networks in microglia, primary human microglia are hard to acquire and intrac- table for many genome-editing, genomic, and high-throughput technologies. The overall objective of this proposal is to determine how AD causal SNPs alter microglia regulatory networks. Using microglia derived from human induced pluripotent stem cells, we will define transcriptional regulatory networks in resting and activated microglia (Aim 1), identify the causal SNPs within each AD GWAS locus (Aim 2), and determine the genes affected by AD-associated SNPs (Aim 3). Accomplishment of the goals set forth here will establish a cell culture model of microglial response to AD stimuli, determine the causal AD variants at each GWAS locus, and identify the genes impacted by AD-associated SNPs. These results will have a positive impact because they will identify the key genes involved in AD pathogenicity, providing a foundation for further studies towards the development of tools to diagnose, prognose, and treat AD.

项目摘要阿尔茨海默病的治疗方案一直难以捉摸，很大程度上是因为分子机制-- 阿尔茨海默病的潜在症状仍不清楚。全基因组关联研究发现了基因组与AD风险增加相关的基因座；然而，这些基因座和基因内的确切因果变异它们的影响一直很难确定。虽然许多证据表明这些变种会改变小胶质细胞的转录调控网络，原代人小胶质细胞很难获得和内. 表中列出了许多基因组编辑、基因组和高通量技术。这样做的总体目标是建议确定AD因果SNPs如何改变小胶质细胞调节网络。使用衍生的小胶质细胞从人类诱导的多能干细胞，我们将定义静息和激活的小胶质细胞(目标1)，识别每个AD Gwas基因座中的原因SNPs(目标2)，并确定受AD相关SNPs影响的基因(目标3)。完成这里提出的目标将确立小胶质细胞对AD刺激反应的细胞培养模型，确定每个GWA的原因AD变异并确定受AD相关SNPs影响的基因。这些结果将产生积极的影响因为他们将确定参与AD致病的关键基因，为进一步研究开发诊断、预测和治疗AD的工具。