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

项目摘要 阿尔茨海默病的治疗选择一直难以捉摸，在很大程度上是因为分子机制， AD的潜在病因尚不清楚。全基因组关联研究（GWAS）揭示了 与AD风险增加相关的基因座;然而，这些基因座和基因中的确切致病变异 它们的影响很难确定。虽然许多证据表明，这些变异改变了 小胶质细胞中的转录调控网络，原代人类小胶质细胞很难获得和intrac， 许多基因组编辑，基因组和高通量技术的表格。本报告的总体目标 这项研究的目的是确定AD因果SNP如何改变小胶质细胞调控网络。使用小胶质细胞衍生的 从人类诱导多能干细胞，我们将定义转录调控网络在休息， 激活的小胶质细胞（目标1），确定每个AD GWAS基因座内的致病SNP（目标2），并确定 受AD相关SNP影响的基因（Aim 3）。实现这里提出的目标将建立 小胶质细胞对AD刺激反应的细胞培养模型，确定每个GWAS的因果AD变体 基因座，并确定受AD相关SNP影响的基因。这些结果将产生积极影响 因为他们将确定参与AD致病性的关键基因，为进一步研究AD提供基础。 研究开发诊断、诊断和治疗AD的工具。

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.