Single-cell Epigenome Analysis of the Alzheimer's Disease Brain

阿尔茨海默病大脑的单细胞表观基因组分析

基本信息

批准号：
10546522
负责人：
Christopher Hartl
金额：
$ 49.95万
依托单位：
EPIGENOME TECHNOLOGIES, INC.
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：
2022-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546522
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer&apos s disease therapy American Astrocytes Atlases Autopsy Biological Assay Biomedical Research Biomedical Technology Biotechnology Brain Catalogs Cells ChIP-seq Chromatin Clinical Code Cognitive Dementia Development Disease Disease associated microglia Exhibits Female Future Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Transcription Genomics Goals Heritability Human Human Genome Individual Investigation Joints Knowledge Late Onset Alzheimer Disease Lead Licensing Link Maps Memory Loss Microglia Molecular Molecular Analysis Mutation Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathologic Pathway interactions Phenotype Prefrontal Cortex Preventive therapy Regression Analysis Regulator Genes Regulatory Element Research Resolution Resources Risk Sampling Signal Transduction Specificity Technology Testing Translating Untranslated RNA Variant brain cell cell type clinical application cognitive function curative treatments design effective therapy epigenome epigenomics genome wide association study high throughput technology histone modification human subject improved male multiple omics novel novel strategies programs research and development response risk variant single-cell RNA sequencing tool transcription factor transcriptome treatment strategy

项目摘要

Title: Single-cell Epigenome Analysis of the Alzheimer’s Disease Brain (PI: Hartl) Alzheimer’s disease (AD) affects more than 6 million American but no cures and few effective treatments are available. Genome-wide association studies (GWAS) have uncovered thousands of segregating mutations that significantly increase AD risk. Most of these variants alter non-protein-coding sequence and lack clear functional annotation, hindering efforts to translate risk-conferring mutations into curative or preventative therapies. Heritability partitioning suggests that these variants likely perturb gene expression in glial cells (especially microglia), ultimately leading to AD pathology. Linking these variants – and their downstream effects – to specific regulatory networks and pathways has been hindered by a lack of cis-regulatory element maps for these major glial cell classes and their subtypes. The proposed study addresses this critical knowledge gap by applying a cutting-edge single cell multi-omic technology to postmortem human brain samples from phenotypically normal donors and AD patients. Specifically, the chromatin accessibility or histone modifications will be interrogated jointly with gene expression at single cell resolution in dorsolateral prefrontal cortex (DLPFC) from multiple donors, to identify and characterize the cell-type-specific gene regulatory elements that drive aberrant cell states and disease-relevant cellular responses in human AD brains. The single cell chromatin state and gene expression atlases from phenotypically normal individuals will be compared to those from AD subjects to determine the brain cell types, genes and regulatory elements that exhibit significant changes in pathological conditions. Finally, the newly generated cell-type resolved epigenome maps will be integrated with public genomic resources to provide functional annotation of the AD risk variants, identify disease-relevant cell types, prioritize genes, transcription factors, and molecular pathways for future mechanistic investigation. Results of the proposed study will provide a much-needed tool for study of AD pathogenesis and development of improved AD therapies.

标题：阿尔茨海默氏病大脑的单细胞表观基因组分析（PI：HARTL）阿尔茨海默氏病（AD）影响了超过600万美国人，但没有治疗方法，很少有有效的治疗方法可用。全基因组关联研究（GWAS）已发现数千种分离突变这大大增加了广告风险。这些变体中的大多数都会改变非蛋白质编码序列，并且缺乏清晰的功能注释，阻碍将风险支配突变转化为治愈性或预防性的努力疗法。遗传力分配表明这些变体可能会在神经胶质细胞中扰动基因表达（尤其是小胶质细胞），最终导致AD病理学。连接这些变体及其下游效果 - 由于缺乏顺式调节元件图而阻碍了特定的监管网络和途径这些主要的神经胶质细胞类及其亚型。拟议的研究解决了通过从表型正常的供体和AD患者。具体而言，染色质可及性或组蛋白修饰将在背外侧前额叶皮层（DLPFC）中与单细胞分辨率的基因表达共同询问从多个供体来识别和表征驱动的细胞类型特异性基因调节元件人类广告大脑中异常细胞状态和疾病与疾病的细胞反应。单细胞染色质状态将来自表型正常个体的基因表达图谱与AD受试者的那些确定脑细胞类型，基因和调节元素，这些元素暴露了病理学的显着变化状况。最后，新生成的细胞类型解决的表观基因组图将与公众集成基因组资源提供AD风险变异的功能注释，识别与疾病相关的细胞类型，优先考虑基因，转录因子和分子途径，以进行未来的机械投资。结果拟议的研究将为AD发病机理研究和改进的发展提供急需的工具广告疗法。