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.

项目摘要/摘要 AD是一种与年龄相关的神经退行性疾病，影响65岁以上的人群的10％。 发作AD（负载）很复杂。多种常见变体通常会以较小的效应大小影响负载。 这些预测的AD风险基因是否以及如何有助于AD发病机理以及哪种变体影响它们 在大多数情况下，表达仍然存在。拟议的研究的总体目标是 提供广告风险基因角色的全面注释，并确定AD休闲变体有助于 通过调节广告风险基因表达AD。我们将：（1）确定并基准测试生物学后果 在IPSC衍生中使用CRISPRI和单细胞RNA-SEQ通过遗传分析鉴定的推定的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。我们还将使用功能进行跟进 （2）对AD相关表型的细胞和类器官的测定，表征增强剂和与AD相关的变体 对于IPSC衍生的海马DG神经元和海马器官中的AD风险基因，（3）阐明了角色 IPSC衍生的兴奋性神经元，小胶质细胞和大脑器官中的增强剂和AD变体的带有 小胶质细胞。拟议的工作将提供对AD风险基因的全面注释，并脱颖而出。 影响基因表达网络和与AD发病机理有关的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。