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

项目摘要/摘要 阿尔茨海默病(AD)是人类痴呆症最常见的原因，随着 年龄。散发性晚发性AD占阿尔茨海默病病例的90%以上，没有明确的记录 这种疾病的家族史。然而，现有的绝大多数转基因和转基因模型都包含了 与痴呆症相关的一个或多个基因上的致病家族突变，代表着一个主要的 限制。RFA-AG-21-003[阿尔茨海默病的新的/非常规动物模型]突出了 需要开发和表征自然发生的可能代表改进的非小鼠AD模型 通过更好地复制人类疾病的病理特征，具有翻译潜力“。我们对RFA做出回应 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造细胞类型- 额叶皮质和海马区与类AD相关的特定表观基因组和转录组图谱 两种自然发生的阿尔茨海默病动物模型的发病机制。这些动物 显示出与人类AD相似的年龄依赖性神经病理和认知障碍，因此 他们是天生的AD模特。由于德古斯和老鼠都是啮齿类动物，因此对德古斯长寿的研究将是 对于哺乳动物内部AD基因调控途径的顺序比较是特别有价值的 与不同的转基因小鼠模型相比，DECUS中常见的自发性AD样特征。当我们 生成与RFA目标一致的资源，拟议的研究将使我们能够制定 比较分析确定非常规动物模型和非常规动物模型中保守的表观遗传学改变 在我们现有的老鼠模型和人类数据库之间架起桥梁。可及染色质的不适应变化 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发病的特异性和跨物种保守机制及AD预防的新靶点 和治疗。这将为人类AD的发病机制提供新的见解。此外 为了在指定的NIH保管库共享基因组数据，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.