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

• 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
• 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' s Disease; Alzheimer' 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

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 AD 背后的主义仍不清楚。全基因组关联研究（GWAS）发现基因组 与 AD 风险增加相关的位点；然而，这些位点和基因内的确切因果变异 它们的影响很难确定。虽然许多证据表明这些变体改变了 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并且难以获取 许多基因组编辑、基因组和高通量技术的表。本次活动的总体目标 该提案旨在确定 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 从人类诱导多能干细胞中，我们将定义静息和静息状态下的转录调控网络 激活的小胶质细胞（目标 1），识别每个 AD GWAS 位点内的因果 SNP（目标 2），并确定 受 AD 相关 SNP 影响的基因（目标 3）。此处设定的目标的实现将建立 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 变异 位点，并鉴定受 AD 相关 SNP 影响的基因。这些结果将产生积极影响 因为他们将鉴定出参与AD致病性的关键基因，为进一步研究提供基础 研究开发诊断、预测和治疗 AD 的工具。