Oligodendrocyte heterogeneity in Alzheimer' s disease

阿尔茨海默病中的少突胶质细胞异质性

• 批准号: 10180000
• 负责人: VIVEK SWARUP
• 金额: $ 188.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180000
• 关键词: 3xTg-AD mouse; ATAC-seq; Affect; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Autopsy; Axon; Behavioral; Binding Proteins; Binding Sites; Bioinformatics; Biology; Brain; Brain Diseases; Brain region; Cell Nucleus; Cell physiology; Cells; Chromatin; Complex; DNA Sequence Alteration; Data; Data Science; Databases; Dependovirus; Disease; Disease Progression; Ensure; Experimental Designs; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Heterogeneity; Human; Immunohistochemistry; In Situ Hybridization; Individual; Light; Maps; Metabolic; Molecular; Molecular Biology; Multiomic Data; Mus; Myelin; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oligodendroglia; Pathogenesis; Pathologic; Pathology; Population; Prefrontal Cortex; Prevalence; Proteomics; Regulatory Element; Reporting; Resolution; Risk Factors; Role; Sampling; Sex Differences; Specimen; Sterols; Systems Biology; Temporal Lobe; Tissues; Translating; base; cell type; cholesterol biosynthesis; differential expression; disorder control; economic cost; epigenomics; experimental study; functional genomics; genetic analysis; genetic manipulation; genome-wide; genomic data; human data; insight; mouse model; multiscale data; new therapeutic target; novel; overexpression; programs; single molecule; transcription factor; transcriptome sequencing; transcriptomics

Project Summary/Abstract Neurodegenerative disease mechanisms encompassing Alzheimer’s disease (AD) are complex and have remained largely unknown to date despite the identification of risk factors and genetic mutations associated with the disease. Oligodendrocytes (ODCs) have critical roles in the central nervous system where they ensheath axons to allow rapid saltatory conduction and also provide metabolic support to neurons. Although a largely homogeneous oligodendrocyte population is thought to execute these functions throughout the brain, recent reports suggests that ODCs are highly diversified cell populations in the brain. Using systems biology approach, that integrates multi-omics data from human pathological specimens and mouse models of AD, this project aims to generate single-cell resolution genome-wide maps of transcriptional and regulatory networks in ODCs associated with AD. The project represents a major advance in the field by taking a comprehensive approach to data-driven discovery to identify highly conserved regulatory programs of AD. In parallel, the project aims to understand the role of sterol regulatory-element binding proteins (SREBPs) in AD using functional genomic approaches. Finally, the project will identify novel cell-type specific transcriptional regulators of AD using cutting edge approaches to data science.

项目总结/摘要 包括阿尔茨海默病（AD）的神经退行性疾病机制是复杂的， 迄今为止，尽管确定了与糖尿病相关的风险因素和基因突变， 这种疾病少突胶质细胞（ODC）在中枢神经系统中具有重要作用， 轴突，以允许快速跳跃式传导，并为神经元提供代谢支持。虽然在很大程度上 同质少突胶质细胞群体被认为在整个大脑中执行这些功能，最近， 报告表明，ODC是大脑中高度多样化的细胞群。利用系统生物学方法， 该项目旨在整合来自人类病理标本和AD小鼠模型的多组学数据 生成ODC中转录和调控网络的单细胞分辨率全基因组图谱 与AD有关。该项目通过采取综合办法， 数据驱动的发现，以确定AD的高度保守的调控程序。与此同时，该项目旨在 了解固醇调节元件结合蛋白（SREBPs）在AD中的作用， 接近。最后，该项目将确定新的细胞类型特异性转录调节AD使用切割 数据科学的边缘方法。

项目成果

Exposure to quasi-ultrafine particulate matter accelerates memory impairment and Alzheimer's disease-like neuropathology in the AppNL-G-F knock-in mouse model.

在 AppNL-G-F 敲入小鼠模型中，接触准超细颗粒物会加速记忆障碍和阿尔茨海默病样神经病理学。

• DOI: 10.1093/toxsci/kfad036
• 发表时间: 2023
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Kilian,JasonG;Mejias-Ortega,Marina;Hsu,Heng-Wei;Herman,DavidA;Vidal,Janielle;Arechavala,RebeccaJ;Renusch,Samantha;Dalal,Hansal;Hasen,Irene;Ting,Amanda;Rodriguez-Ortiz,CarlosJ;Lim,Siok-Lam;Lin,Xiaomeng;Vu,Joan;Saito,Takashi
• 通讯作者: Saito,Takashi