Functional characterization of Alzheimer's disease associated genetic variants

阿尔茨海默病相关基因变异的功能特征

• 批准号: 10190753
• 负责人: Li Gan
• 金额: $ 83.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190753
• 关键词: 3-Dimensional; ATAC-seq; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnostic; Alzheimer' s disease patient; Alzheimer' s disease risk; Biological Assay; Biological Testing; Brain; CRISPR/Cas technology; Cell Culture Techniques; Cell Line; Cell model; Cell physiology; Cells; Chromatin; Code; Complex; Data; Development; Diagnostic Procedure; Disease; Distal; Elements; Enhancers; Epigenetic Process; Etiology; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomic approach; Goals; Hippocampus (Brain); Human; Human Genome; Individual; Investigation; Knock-in; Knowledge; Light; Link; Linkage Disequilibrium; Location; Maps; Mediating; Methods; Microglia; Mutation; Neurodegenerative Disorders; Neurons; Nucleic Acid Regulatory Sequences; Organoids; Pathogenesis; Phenotype; Play; Population; Predisposition; Process; Promoter Regions; Regulatory Element; Reporter; Research Design; Signal Transduction; System; Testing; Untranslated RNA; Variant; age related neurodegeneration; causal variant; cell type; combinatorial; excitatory neuron; functional genomics; genetic variant; genome editing; genome wide association study; genome-wide; human old age (65+); improved; induced pluripotent stem cell; insight; new therapeutic target; novel; novel therapeutic intervention; personalized medicine; precision medicine; promoter; single-cell RNA sequencing; stem cells; tool; transcriptome sequencing

Project Summary/Abstract Alzheimer's disease (AD) is a devastating complex neurological degenerative disorder affecting 10% of people over 65 with no cure. The overarching goal of the proposed study is to identify and functionally characterize AD-associated SNPs utilizing novel functional genomic approaches and iPSC-derived cellular models. Our plans include: (1) Determine the functional significance of candidate SNPs in three iPSC-drived 2D AD relevant cell types. (2) Identify genes regulated by distal non-coding SNPs in three iPSC-drived 2D AD relevant cell types. (3) Test the biological consequences of high confidence AD rSNPs from (1) and (2) in isogenic iPSC- derived 2D cell cultures and 3D minibrain organoids. The designed study will be very first comprehensive investigation of AD associated SNPs, thus will shed light on how non-coding genetic variations contribute to AD. Obtaining knowledge for the fundamental genetic mechanisms of AD will expand our horizons to develop improved preventative and diagnostic methods, and also yield targets for novel therapeutic interventions, ultimately leading to a cure for AD.

项目摘要/摘要 阿尔茨海默病(AD)是一种破坏性的复杂神经退行性疾病，影响10%的人 65岁以上，无法治愈。拟议研究的总体目标是确定和确定功能特征 利用新的功能基因组方法和IPSC衍生的细胞模型的AD相关SNPs。我们的 计划包括：(1)确定候选SNP在IPSC驱动的三个相关2D AD中的功能意义 单元类型。(2)在IPSC驱动的2D AD相关细胞中发现远端非编码SNPs调控的基因 类型。(3)测试(1)和(2)中的高置信度AD rSNPs在等基因IPSC中的生物学后果- 衍生2D细胞培养和3D迷你脑器官。这项设计的研究将是第一次全面的 因此，对AD相关SNPs的研究将有助于揭示非编码遗传变异是如何影响AD的 广告。对阿尔茨海默病的基本遗传机制的了解将拓展我们的视野 改进预防和诊断方法，并为新的治疗干预措施产生目标， 最终导致了AD的治愈。

项目成果

High-throughput PRIME-editing screens identify functional DNA variants in the human genome.

• DOI: 10.1016/j.molcel.2023.11.021
• 发表时间: 2023-12
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Xingjie Ren;Han Yang;Jovia L. Nierenberg;Yifan Sun;Jiawen Chen;Cooper Beaman;Thu Pham;Mai Nobu

High throughput PRIME editing screens identify functional DNA variants in the human genome.

高通量 PRIME 编辑屏幕可识别人类基因组中的功能性 DNA 变异。

• DOI: 10.1101/2023.07.12.548736
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Ren,Xingjie;Yang,Han;Nierenberg,JoviaL;Sun,Yifan;Chen,Jiawen;Beaman,Cooper;Pham,Thu;Nobuhara,Mai;Takagi,MayaAsami;Narayan,Vivek;Li,Yun;Ziv,Elad;Shen,Yin
• 通讯作者: Shen,Yin