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：
10682624
负责人：
Bing Ren
金额：
$ 118.17万
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/10682624
关键词：
9 year old ATAC-seq Acceleration Age Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model American 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 Disease associated microglia Elderly Enhancers Epigenetic Process Exhibits Gene Expression Genes Genome Goals Health Hi-C Hippocampus Human Impaired cognition Joints Knock-in Late Onset Alzheimer Disease Ligation Maps Methods 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 abeta accumulation age related aged behavior measurement behavioral impairment brain cell cell type comparative computational pipelines data modeling data sharing epigenome epigenomic profiling epigenomics frontal lobe genome-wide genomic data histopathological examination human disease human old age (65+)hyperphosphorylated tau improved insight mouse model multiple omics neural circuit neuropathology novel therapeutics promoter repository single nucleus RNA-sequencing transcriptome transcriptome sequencing transcriptomics translational potential validation studies

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.

项目概要/摘要阿尔茨海默氏病（AD）是人类痴呆症的最常见原因，随着年龄的增长，痴呆症会逐渐恶化。 90%以上的阿尔茨海默病病例是散发性迟发性阿尔茨海默病，但没有明确的记录。然而，绝大多数现有的转基因和基因敲入模型都包含该疾病的家族史。与痴呆症相关的一个或多个基因的致病家族突变，代表了一种主要的 RFA-AG-21-003 [阿尔茨海默病的新/非常规动物模型] 强调了这一点。需要开发和表征自然发生的“AD 非鼠模型”，该模型可能代表改进的 AD 通过更好地复制人类疾病的病理特征来发挥转化潜力”我们对 RFA 做出了回应。应用我们团队开发的单细胞表观基因组和转录组技术来创建细胞类型- 额叶皮层和海马体中与 AD 样相关的特定表观基因组和转录组图谱两种自然发生的AD动物模型的发病机制：八齿鼠和家犬。显示出与人类 AD 相似的年龄依赖性神经病理学和认知障碍，因此由于八齿鼠和小鼠都是啮齿动物，因此对长寿八齿鼠的研究将是自然的 AD 模型。对于 AD 基因调控途径的哺乳动物内顺序比较特别有价值与不同的转基因小鼠模型相比，八齿鼠的自发性 AD 样特征是常见的。生成与 RFA 目标一致的资源，拟议的研究将使我们能够开发比较分析以确定非常规动物模型中保守的表观遗传改变连接我们现有的小鼠模型和人类数据库中可及染色质的适应不良变化。疾病相关细胞类型的可及性、染色质组织和基因表达将揭示物种- AD发病机制的特异性和跨物种保守机制以及AD预防的新靶点此外，这将为人类 AD 发病机制提供新的见解。为了在指定的 NIH 存储库共享基因组数据，资源将在我们的 UCI 共享和管理神经回路映射中心。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatial maps and oscillations in the healthy hippocampus of Octodon degus, a natural model of sporadic Alzheimer's disease.

八齿鼠健康海马体的空间图和振荡，八齿鼠是散发性阿尔茨海默病的自然模型。

DOI：
发表时间：
2022-05-05
期刊：
影响因子：
4.6
作者：
Mugnaini, Matias;Polania, Diana;Diaz, Yannina;Ezquer, Marcelo;Ezquer, Fernando;Deacon, Robert M J;Cogram, Patricia;Kropff, Emilio
通讯作者：
Kropff, Emilio