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：
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
项目类别：
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&apos s Disease Alzheimer&apos 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

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 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.

项目概要/摘要阿尔茨海默病（AD）是老年人痴呆症的主要原因，也是最常见的年龄- 相关的神经退行性疾病，影响着全球约 5600 万人，尽管其遗传性很高。（估计范围为 60-80%）和许多遗传变异（存在于整个基因组的数十个基因座中）被识别根据全基因组关联研究（GWAS），我们对潜在遗传机制的了解仍然存在揭示 AD 的病理生理机制非常具有挑战性。为了提高我们对 AD 的机械理解，我们将首先获取并协调各种内部的、受保护的和公共数据，包括批量和单细胞 RNA-seq 数据、GWAS 摘要统计、阵列然后我们将分析基因分型和全基因组测序数据以及功能基因组数据。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这些假设将通过我们的实验技术得到验证。验证将在 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，因为以及 iPSC 衍生的脑类器官，涉及多种细胞类型，包括神经元、星形胶质细胞和在这些 iPSC 衍生的细胞和类器官模型中，我们将利用 CRISPRi 以及基因敲入。扰乱最有前途的假定因果调控 DNA 元件的实验技术，以及通过测量一系列分子和细胞表型（包括基因表达）来评估影响和 AD 相关的生理表型。