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

项目总结/摘要 阿尔茨海默氏病（AD）是人类痴呆症的最常见原因，其逐渐伴随有 年龄散发性迟发性AD占阿尔茨海默病病例的90%以上，没有明确的记录。 疾病的家族史。然而，绝大多数现有的转基因和基因敲入模型结合了 一个或多个与痴呆相关的基因中的致病家族性突变，代表了一个主要的 限制. RFA-AG-21-003 [新型/非常规阿尔茨海默病动物模型]强调了 需要开发和表征自然发生的“非鼠AD模型”， 通过更好地复制人类疾病的病理特征来提高翻译潜力”。我们响应RFA 应用我们团队开发的单细胞表观基因组和转录组技术， 额叶皮层和海马中特异性表观基因组和转录组图谱与AD样 在两种自然发生的AD动物模型中的发病机制：Deddon degus和Canis familiaris。这些动物 显示出与在人类AD中观察到的那些相似的年龄依赖性神经病理学和认知损害，因此 它们是自然的AD模型。由于degus和小鼠都是啮齿类动物，因此对长寿degus的研究将是 特别是有价值的哺乳动物内的顺序比较，其中AD基因调控途径是 常见于degus与不同转基因小鼠模型中的自发性AD样特征。虽然我们 产生与RFA目标一致的资源，拟议的研究将使我们能够制定一个 比较分析以确定非常规动物模型中保守的表观遗传改变， 连接我们现有的小鼠模型和人类数据库。可及染色质的适应不良变化 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- 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 和治疗。这将为人类AD发病机制提供新的见解。此外 为了在指定的NIH保存库共享基因组数据，资源将在我们的UCI共享和管理 神经回路映射中心。

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.