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

基本信息

批准号：
10670502
负责人：
Li Gan
金额：
$ 134.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670502
关键词：
3-Dimensional Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Astrocytes Base Pairing Biological Assay Biological Process Brain Brain imaging CRISPR interference Cells Cerebrum Chromatin Conformation Capture and Sequencing Chromatin Loop Clustered Regularly Interspaced Short Palindromic Repeats Complex Computational Technique Computing Methodologies 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 Neuraxis 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 base bioinformatics tool brain cell case control 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 genomic data imaging genetics induced pluripotent stem cell programs promoter single-cell RNA sequencing statistics therapeutic development transcriptome transcriptome sequencing transcriptomics whole genome

项目摘要

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 myriads of 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/摘要阿尔茨海默氏病（AD）是老年和最普遍的痴呆症的主要原因 - 相关的神经退行性疾病，全球影响约5600万人。尽管具有很高的遗传力（估计为60-80％）和许多遗传变异（居住在基因组中的数十个基因座）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的。发现广告潜在的病理生理机制被证明是高度挑战的。到提高我们对AD的机械理解，我们将首先获得并协调各种内部，受到保护和公共数据，包括散装和单细胞RNA-seq数据，GWAS摘要统计信息，数组基因分型和整个基因组测序数据以及无数功能基因组数据。然后我们会使用一套计算方法和生物信息学工具来分析它们，以生成细胞类型特异性机械假设。这些假设将通过实验技术得到验证。我们的验证将在IPSC衍生的神经元（部分兴奋性神经元和小胶质细胞）中进行，为以及在IPSC衍生的脑类器官中，涉及潜水细胞类型，包括神经元，星形胶质细胞和小胶质细胞。在这些IPSC衍生的细胞和类器官模型中，我们将利用CRISPRI和敲门实验技术，以扰动最有前途的因果关系调节性DNA元素，并通过测量包括基因表达的分子和细胞表型来评估影响和与AD相关的生理表型。