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：
10382389
负责人：
Todd Jonathan Cohen
金额：
$ 73.88万
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/10382389
关键词：
3-Dimensional Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Base Pairing Binding Biological Assay Brain Cell Culture Techniques Chromatin Chromatin Loop Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Data Set Diagnosis Disease Distal Enhancers Event Foundations Genes 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 Single Nucleotide Polymorphism Speed Stimulus TREM2 gene Techniques Testing Transcriptional Regulation Untranslated RNA Variant Work base biological systems brain cell 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氏病的治疗选择是难以捉摸的，这在很大程度上是因为分子机甲 - 尚不清楚的广告基础知识尚不清楚。全基因组关联研究（GWAS）具有发现的基因组与AD风险增加相关的基因座；但是，这些基因座和基因中的确切因果变体它们很难确定。尽管许多证据表明这些变体改变了小胶质细胞中的转录调节网络，原发性小胶质细胞很难获取和内部用于许多基因组编辑，基因组和高通量技术的表。总体目标建议是确定AD因果SNP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中，我们将在静止和活化的小胶质细胞（AIM 1），识别每个AD GWAS基因座中的因果SNP（AIM 2），并确定受广告相关SNP影响的基因（AIM 3）。实现这里设定的目标将建立小胶质反应对AD刺激的细胞培养模型，确定每个GWAS的因果AD变体基因座，并确定受广告相关SNP影响的基因。这些结果将产生积极的影响因为他们将确定与广告致病性有关的关键基因，从而为进一步的基础提供了基础研究开发诊断，进步和治疗AD的工具的研究。