Brain Single-nuclei and iPS-derived cells transcriptomic analysis to define the contribution of neuronal and glial pathw

脑单核和 iPS 衍生细胞转录组分析以确定神经元和神经胶质通路的贡献

基本信息

批准号：
10302162
负责人：
Carlos Cruchaga
金额：
$ 71.91万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302162
关键词：
Address Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Astrocytes Atlases Biological Process Biology Brain Brain region CRISPR/Cas technology Cell Nucleus Cells Chemistry Cholesterol Homeostasis Collection Communities Complex DNA Sequence Alteration Data Data Set Degradation Pathway Disease Etiology Frontotemporal Dementia GABA Receptor Gene Expression Genes Genetic Genetic Risk Gliosis Human Immune response Immune system Induced pluripotent stem cell derived neurons Inherited Knowledge Portal Lead Link MAPT gene Microglia Molecular Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Parietal Lobe Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pattern Population Prevention Process RNA RNA analysis Regulator Genes Research Research Design Resolution Resources Risk Small Nuclear RNA Structure TREM2 gene Translating Validation Variant apolipoprotein E-4 brain cell brain tissue cell type cohort data portal defined contribution differential expression digital disease heterogeneity excitatory neuron genetic variant genome editing genome wide association study high risk human RNA sequencing human data human tissue induced pluripotent stem cell inhibitory neuron innovation insight mutation carrier neuron loss novel presenilin-1 presenilin-2 risk variant sex synaptic function tau-1 transcriptome sequencing transcriptomics web interface

Address Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Astrocytes Atlases Biological Process Biology Brain Brain region CRISPR/Cas technology Cell Nucleus Cells Chemistry Cholesterol Homeostasis Collection Communities Complex DNA Sequence Alteration Data Data Set Degradation Pathway Disease Etiology Frontotemporal Dementia GABA Receptor Gene Expression Genes Genetic Genetic Risk Gliosis Human Immune response Immune system Induced pluripotent stem cell derived neurons Inherited Knowledge Portal Lead Link MAPT gene Microglia Molecular Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Parietal Lobe Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pattern Population Prevention Process RNA RNA analysis Regulator Genes Research Research Design Resolution Resources Risk Small Nuclear RNA Structure TREM2 gene Translating Validation Variant apolipoprotein E-4 brain cell brain tissue cell type cohort data portal defined contribution differential expression digital disease heterogeneity excitatory neuron genetic variant genome editing genome wide association study high risk human RNA sequencing human data human tissue induced pluripotent stem cell inhibitory neuron innovation insight mutation carrier neuron loss novel presenilin-1 presenilin-2 risk variant sex synaptic function tau-1 transcriptome sequencing transcriptomics web interface

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项目摘要

Abstract Alzheimer’s disease (AD) is a complex and heterogenous condition in which multiple molecular pathways are disrupted in different cell-types and lead to disease. Genetic findings indicate that amyloid-beta protein clearance and degradation pathways, cholesterol metabolism and the immune system are associated with AD etiology. However, the specific mechanism, genes and molecular networks have not yet been completely identified. Single-nuclei transcriptomic (snRNA-seq) data from human brains provides a detailed molecular atlas to study the pathways dysregulated in AD. We propose to deepen our understanding of the genes, network and molecular pathways associated with AD by sequencing a high-number of neuronal and glial cells (approximately 3.3 million cells) from human brain carriers of key genetic mutations and high risk variants, non-carrier sporadic AD cases and neuropath-free controls. We will leverage a unique collection of human tissue from the Dominantly Inherited Alzheimer Network and Knight-ADRC brain banks, and select +220 brains to perform systematic cell- type specific transcriptomic analyses. This is a unique and innovative study designed to analyze cell-specific transcriptomic dysregulation in carriers of high effect risk variants (TREM2 and APOE) and fully penetrant pathogenic mutations in APP/PSEN1/PSEN2 and by comparing them to sporadic AD cases and neuropath-free controls. This is a powerful approach to address disease heterogeneity, and will provide highly informative insights into the biology and pathology of neurodegeneration. Replication of these findings will be performed in snRNA-seq data from induced pluripotent stem cell derived neurons, astrocytes, and microglia-like cells that will be genome edited to add/remove genetic variants, as well as datasets that are being publicly released. Finally, we will create a knowledge portal in which all of the processed snRNA-seq data from our study will be harmonized with that of other research groups to provide a comprehensive molecular atlas that will provide additional insights into the biology and pathology of AD for the entire research community.

抽象的阿尔茨海默氏病（AD）是一种复杂而异质的疾病，其中多个分子途径是以不同的细胞类型破坏并导致疾病。遗传发现表明淀粉样蛋白β蛋白清除率和降解途径，胆固醇代谢和免疫系统与AD病因有关。但是，尚未完全鉴定出特定的机制，基因和分子网络。来自人类大脑的单核转录组（SNRNA-SEQ）数据提供了一个详细的分子地图集 AD中的途径失调。我们建议加深对基因，网络和网络的理解通过对高数量的神经元和神经胶质细胞进行测序（大约 330万细胞）来自关键遗传突变和高风险变异的人脑载体，非携带者Spuradic AD病例和无神经病例对照。我们将利用主要的人类组织的独特集合继承的阿尔茨海默氏症网络和骑士 - ADRC脑库，选择+220大脑以执行系统细胞 - 键入特定的转录组分析。这是一项旨在分析细胞特异性的独特而创新的研究高效风险变体（TREM2和APOE）和完全渗透物的载体中的转录组失调 APP/PSEN1/PSEN2中的致病突变，并通过将其与零星的AD病例和无神经病例进行比较控件。这是解决疾病异质性的强大方法，并将提供丰富的信息对神经退行性的生物学和病理学的见解。这些发现的复制将在来自诱导多能干细胞衍生的神经元，星形胶质细胞和小胶质细胞样细胞的SnRNA-Seq数据，这些数据将会要编辑基因组以添加/删除遗传变异，以及正在公开发布的数据集。最后，我们将创建一个知识门户与其他研究小组一起提供一个全面的分子图集，该地图集将提供其他见解进入整个研究界的AD的生物学和病理学。