Study of Selective Cell and System Vulnerability in Alzheimer's Disease

阿尔茨海默氏病选择性细胞和系统脆弱性的研究

• 批准号: 10662925
• 负责人: Li Gan
• 金额: $ 135.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662925
• 关键词: 3-Dimensional; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Astrocytes; Base Pairing; Biological Assay; Biological Process; Brain; Brain imaging; CRISPR interference; Cells; Central Nervous System; Cerebrum; Chromatin Conformation Capture and Sequencing; Chromatin Loop; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Computational Technique; Computing Methodologies; Creativeness; DNA; Data; Dementia; Disease; Distal; Elderly; Elements; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genotype; Heritability; Individual; Knock-in; Knowledge; Measurement; Measures; Mediating; Microglia; Modeling; Molecular; Neurobiology; Neurons; Nucleic Acid Regulatory Sequences; Organoids; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Population; Prosencephalon; Protocols documentation; Regulation; Regulator Genes; Resolution; Role; Sampling; Signal Transduction; System; Techniques; Technology; Testing; Tissues; Transcriptional Regulation; Validation; Variant; Work; age related neurodegeneration; bioinformatics tool; brain cell; candidate validation; causal variant; cell type; computational suite; differential expression; epigenomics; excitatory neuron; experimental study; follow-up; functional genomics; genetic variant; genome sequencing; genome wide association study; genome-wide analysis; genomic data; imaging genetics; induced pluripotent stem cell; programs; promoter; single-cell RNA sequencing; statistics; therapeutic development; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a leading cause of dementia among the elderly and the most prevalent age- related neurodegenerative disease, affecting ~56 million individuals worldwide. Despite of its high heritability (estimates ranging 60-80%) and many genetic variants (residing in tens of loci across the genome) identified from genome-wide association studies (GWAS), our knowledge of the underlying genetic mechanisms remains limited. Uncovering pathophysiological mechanisms underlying AD proves to be highly challenging. To advance our mechanistic understanding of AD, we will first acquire and harmonize various in-house, protected and public data, encompassing bulk and single cell RNA-seq data, GWAS summary statistics, array genotyping and whole genome sequencing data, as well as functional genomic data. We will then analyze them using a suite of computational methods and bioinformatics tools to generate cell-type-specific mechanistic hypotheses. These hypotheses will be validated through experimental technologies. Our validations will be carried out in iPSC-derived neural cells (particularly excitatory neurons and microglia), as well as in iPSC-derived brain organoids involving diverse cell types including neurons, astrocytes, and microglia. In these iPSC-derived cells and organoids models, we will leverage CRISPRi as well as knock-in experimental technologies to perturb the most promising putatively causal regulatory DNA elements, and evaluate the impact by measuring a cascade of molecular and cellular phenotypes including gene expression and AD related physiological phenotypes.

项目摘要/摘要 阿尔茨海默病（AD）是老年人痴呆的主要原因，并且是最普遍的年龄- 相关的神经退行性疾病，影响全球约5600万人。尽管它的遗传性很高 （估计范围为60-80%）和许多遗传变异（存在于基因组中的数十个位点） 从全基因组关联研究（GWAS）中，我们对潜在遗传机制的了解仍然存在， 有限公司揭示AD的病理生理机制是极具挑战性的。到 为了提高我们对AD的机械理解，我们将首先获取和协调各种内部、受保护的 和公共数据，包括批量和单细胞RNA测序数据、GWAS汇总统计数据、阵列 基因分型和全基因组测序数据，以及功能基因组数据。我们将分析 他们使用一套计算方法和生物信息学工具来生成细胞类型特异性的 机械假说这些假设将通过实验技术得到验证。我们 将在iPSC衍生的神经细胞（特别是兴奋性神经元和小胶质细胞）中进行验证， 以及iPSC衍生的脑类器官，涉及不同的细胞类型，包括神经元，星形胶质细胞， 小胶质细胞在这些iPSC衍生的细胞和类器官模型中，我们将利用CRISPRi以及敲入 干扰最有希望的致腐调节DNA元件的实验技术，以及 通过测量包括基因表达在内的一系列分子和细胞表型来评估影响 和AD相关的生理表型。