Elucidate the roles of Alzheimer's disease risk genes and variants in gene expression and AD-related phenotypes

阐明阿尔茨海默病风险基因和变异在基因表达和 AD 相关表型中的作用

• 批准号: 10538968
• 负责人: Li Gan
• 金额: $ 371.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538968
• 关键词: Abeta synthesis; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Benchmarking; Biological; Biological Assay; Biological Process; CRISPR interference; Cell physiology; Cells; Cellular Assay; Cerebrum; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complement 3d Receptors; Complex; Cytoplasmic Granules; Data Set; Endocytosis; Enhancers; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Hippocampus (Brain); Immune response; Individual; Late Onset Alzheimer Disease; Measures; Mediating; Medical; Meta-Analysis; Microglia; Modeling; Molecular; Nature; Neurons; Organoids; Pathogenesis; Pathway interactions; Phenotype; Physical Function; Physiological; Play; Population; Proteins; Regulatory Element; Research Personnel; Rest; Role; Small Nuclear RNA; System; TREM2 gene; Testing; Tissues; Untranslated RNA; Variant; Work; age related neurodegeneration; base; causal variant; cell type; epigenome editing; epigenomics; excitatory neuron; follow-up; frontal lobe; gene network; genetic analysis; genetic information; genetic variant; genome editing; genome wide association study; genomic locus; granule cell; improved; in vivo; induced pluripotent stem cell; lipid metabolism; new therapeutic target; prime editing; risk prediction; risk variant; single-cell RNA sequencing; success; transcriptome

Project Summary/Abstract AD is an age-related neurodegenerative disorder affecting 10% of the population over 65. The genetics of Late- onset AD (LOAD) is complex. Multiple common variants usually influence LOAD with smaller effect sizes. Whether and how these predicted AD risk genes contribute to AD pathogenesis and which variant affect their expression remain, for the most part, to be characterized. The overarching goal of the proposed study is to provide a comprehensive annotation of roles for AD risk genes and determine AD casual variants contribute to AD via modulating AD-risk gene expression. We will: (1) determine and benchmark the biological consequences of putative AD risk genes identified by genetic analysis using CRISPRi and single-cell RNA-seq in iPSC-derived excitatory neurons, hippocampal dentate granule cells, and microglia. We will also follow up using functional assays in cells and organoids for AD-related phenotypes, (2) characterize enhancers and AD-associated variants for AD risk genes in iPSC-derived hippocampal DG neurons and hippocampal organoids, (3) elucidate the roles of enhancers and AD variants in iPSC-derived excitatory neurons, microglia, and cerebral organoids with microglia. The proposed work will provide a comprehensive annotation of AD risk genes and demystify AD- causal variants affecting gene expression networks and cellular functions related to AD pathogenesis. The success of our proposal will be an essential step towards better risk prediction and new therapeutic targets in AD.

项目概要/摘要 AD 是一种与年龄相关的神经退行性疾病，影响 65 岁以上人口的 10%。 起始 AD (LOAD) 很复杂。多个常见变体通常会以较小的效应大小影响 LOAD。 这些预测的 AD 风险基因是否以及如何促成 AD 发病机制，以及哪些变异影响它们 在很大程度上，表达仍有待表征。拟议研究的总体目标是 提供 AD 风险基因作用的全面注释，并确定 AD 偶然变异对 AD 的影响 AD 通过调节 AD 风险基因表达。我们将：(1) 确定生物学后果并对其进行基准测试 使用 CRISPRi 和单细胞 RNA-seq 在 iPSC 衍生的基因分析中鉴定出的推定 AD 风险基因 兴奋性神经元、海马齿状颗粒细胞和小胶质细胞。我们也会跟进使用功能 在细胞和类器官中检测 AD 相关表型，(2) 表征增强子和 AD 相关变异 对于 iPSC 来源的海马 DG 神经元和海马类器官中的 AD 风险基因，(3) 阐明其作用 iPSC 衍生的兴奋性神经元、小胶质细胞和脑类器官中的增强子和 AD 变异体 小胶质细胞。拟议的工作将提供 AD 风险基因的全面注释并揭开 AD 的神秘面纱。 影响与 AD 发病机制相关的基因表达网络和细胞功能的因果变异。这 我们提案的成功将是朝着更好的风险预测和新的治疗目标迈出的重要一步 广告。