Comparative Single-Cell Epigenomic Analysis of AD-like Pathogenesis in Unconventional Animal Models

非常规动物模型中 AD 样发病机制的比较单细胞表观基因组分析

基本信息

批准号：
10281740
负责人：
Carl Wayne Cotman
金额：
$ 122.35万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2021-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10281740
关键词：
9 year old ATAC-seq Age Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid beta-Protein Anatomy Animal Disease Models Animal Model Animals Astrocytes Atlases Behavior Biological Assay Brain Brain region Canis familiaris Categories Cell Nucleus Cells Cerebral Amyloid Angiopathy ChIP-seq Chilean Chromatin Cognitive Complement DNA DNA Methylation DNA methylation profiling Data Data Set Databases Dementia Development Disease Elderly Enhancers Epigenetic Process Exhibits Gene Expression Genes Genome Goals Health Hi-C Hippocampus (Brain)Human Impaired cognition Joints Knock-in Late Onset Alzheimer Disease Ligation Maps Methods Microglia Modeling Molecular Molecular Target Mus Mutation Nerve Degeneration Neurons Octodon Octodon degus Pathogenesis Pathologic Prefrontal Cortex Publishing Recording of previous events Regulator Genes Regulatory Pathway Research Research Personnel Resolution Resources Rodent Sampling Senile Plaques Technology Testing Transgenic Mice Transgenic Organisms United States National Institutes of Health Variant Work age related aged base behavior measurement behavioral impairment brain cell cell type comparative computational pipelines data modeling data sharing epigenome epigenomics frontal lobe genome-wide genomic data human disease human old age (65+)improved insight mouse model multiple omics neural circuit neuropathology novel therapeutics promoter repository tau Proteins transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary / Abstract Alzheimer's disease (AD) is the most common cause of human dementia that progressively worsens with age. Sporadic late-onset AD accounts for more than 90 percent of Alzheimer’s cases without clear documented familial history of the disease. However, the vast majority of existing transgenic and knock-in models incorporate disease-causing familial mutations in one or more genes associated with dementias, representing a major limitation. The RFA-AG-21-003 [New/Unconventional Animal Models of Alzheimer’s Disease] highlights the need to develop and characterize naturally occurring “non-murine models of AD that may represent improved translational potential by better replicating pathological features of the human disease”. We respond to the RFA to apply single cell epigenomic and transcriptomic technologies developed by our team to create cell-type- specific epigenome and transcriptome maps in frontal cortex and hippocampus that are associated with AD-like pathogenesis in two naturally occurring AD animal models: Octodon degus and Canis familiaris. These animals show age-dependent neuropathology and cognitive impairment similar to those observed in human AD, thus they are natural AD models. As both degus and mice are rodents, the studies of long-lived degus will be particularly valuable for a within-mammalian order comparison of which AD gene regulatory pathways are common to spontaneous AD-like features in degus versus different transgenic mouse models. While we generate the resources in alignment with the RFA goals, the proposed research will allow us to develop a comparative analysis to determine conserved epigenetic alterations in the unconventional animal models and bridge our existing databases of mouse models and humans. Maladaptive changes in accessible chromatin accessibility, chromatin organization and gene expression in disease relevant cell types will reveal species- specific and cross-species conserved mechanisms of AD pathogenesis, as well as new targets for AD prevention and treatment. This will provide new insights into the mechanisms of AD pathogenesis in humans. In addition to genome data sharing at the designated NIH depository, resources will be shared and curated at our UCI Center for Neural Circuit Mapping.

项目摘要 /摘要阿尔茨海默氏病（AD）是人类痴呆的最常见原因，它逐渐恶化年龄。零星的晚发广告占阿尔茨海默氏症案件的90％以上，没有清晰记录该疾病的家族史。但是，绝大多数现有的转基因和敲门模型都包含与痴呆症相关的一个或多个基因中引起疾病的家庭突变，代表一个主要的基因局限性。 RFA-AG-21-003 [阿尔茨海默氏病的新/非常规动物模型]突出了需要开发和表征自然发生的“ AD的非毛线模型，可能代表改进的AD模型通过更好地复制人类疾病的病理特征的翻译潜力”。我们对RFA做出反应应用我们的团队开发的单细胞表观基因组学和转录组技术来创建细胞类型额叶皮质和海马中的特定表观基因组和转录组图与AD样有关两种天然发生的AD动物模型的发病机理：八度摄氏和Canis Familyis。这些动物显示年龄依赖性的神经病理学和认知障碍类似于人类AD中观察到的障碍它们是天然广告模型。由于DEGUS和小鼠都是啮齿动物，因此长寿命的研究将是对于AD基因调节途径的哺乳动物内秩序比较特别有价值在DEGUS与不同的转基因小鼠模型中具有赞助的AD样特征共有。当我们与RFA目标一致生成资源，拟议的研究将使我们能够开发一个比较分析以确定非常规动物模型中保守的表观遗传改变和弥合我们现有的鼠标模型和人类数据库。适应不良的染色质变化疾病相关细胞类型中的可及性，染色质组织和基因表达将揭示物种 - 特定和跨物种构成了AD发病机理的机制，以及预防AD的新目标和治疗。这将为人类AD发病机理的机制提供新的见解。此外为了在指定的NIH存款处共享基因组数据，将在我们的UCI上共享和策划资源神经电路映射中心。