Integrating multidimensional genomic data to discover clinically-relevant predictive models-Alzheimer's Supplement

基因组不稳定(GIN)是衰老的主要标志，这是已知的两者最大的风险因素 阿尔茨海默病(AD)和癌症。因为对于哪种杜松子酒的衡量标准是最多的 在生物学和临床上相关的，在我们的母项目中，我们正在测试GIN指标并开发工具 在癌症中评估GINS的重复性。我们的方法旨在实现技术、平台和 疾病不可知，因此也应适用于AD。到目前为止，我们的重点是染色体。 不稳定性(CIN，染色体数目和结构改变；例如，断点总数、碱基百分比 拷贝数变异、全功能非整倍体等。)和DNA甲基化不稳定性(dNaM，例如， CpG岛甲基化表型；CIMP，广泛改变的启动子甲基化，密度甲基化到 非甲基化CPGS等)。在癌症方面，我们和其他人已经证明杜松子酒与疾病病因和 进展，治疗反应，是一个潜在的疾病生物标志物。而AD动物模型证实 DNA完整性影响神经元的发育、功能和维持，并进一步影响人类衰老研究 杜松子酒在大脑退化中的作用，目前尚不清楚杜松子酒在AD中的作用。迫切需要评估 AD特异性杜松子酒，特别是作为潜在的精确治疗靶点和定义治疗的早期生物标志物 窗户。我们的跨学科研究团队拥有AD、衰老、基因组不稳定、癌症、基因组学和数据 他拥有专业的科学知识，并具备开展这些研究的条件。我们的长期研究目标是 了解杜松子酒在多种情况下的衰老背景下的作用，以及杜松子酒如何进一步促进 疾病的病因、进展和治疗。在这里，我们提出了演示的第一步 我们将其他疾病的方法学应用于公开的AD人类和小鼠数据，并 将得到的杜松子酒档案与我们父母奖中的癌症数据分析进行比较。我们假设这将是 确定AD患者CIN(目标1)和dNaM不稳定(目标2)的程度和类型。至关重要的是，我们将 演示我们的方法和所获得的知识有多普遍，添加AD示例和小插曲 我们正在开发的工具，并比较不同疾病(AD和癌症)、不同物种(人类和 老鼠)，与性别和年龄有关。此外，我们还将从以下位置生成基因和dNaM数据 3xTg-AD小鼠海马体(AD相关脑组织)、胫前肌(作为哨兵器官)和 血浆(作为循环因子)以研究杜松子酒作为AD生物标志物的作用。重要的是，有了这份补充材料，我们将 通过扩展我们现有的非AD来展示家长奖励方法和知识的概括性 NHGRI奖有一个广告重点。这项工作还将促进AD中的其他活动和协作 和相关的痴呆症，为未来几个针对GING作用的赠款提案提供初步数据 在衰老作为一种普遍的疾病机制中，在AD的发病机制中，对于药物的再利用和共同的病因 癌症和阿尔茨海默病之间的研究，以及关于GINS作为外周或循环生物标志物的用途。

Genomic instability (GIN) is a primary hallmark of aging, which is the greatest known risk factor for both Alzheimer’s disease (AD) and cancer. Because there is no consensus on which measures of GIN are most biologically and clinically relevant, in our parent project we are testing GIN metrics and developing tools for assessing GINs reproducibly across cancer. Our approaches are designed to be technology-, platform-, and disease-agnostic and therefore should also apply to AD. Our focus, thus far, has been on chromosomal instability (CIN, altered chromosome number and structure; e.g., total number of breakpoints, percent of bases with copy number variation, total functional aneuploidy, etc.) and DNA methylation instabilities (DNAm, e.g., CpG island methylator phenotype; CIMP, widespread altered promoter methylation, density of methylated to non-methylated CpGs, etc.). In cancer we and others have shown GIN is linked to disease etiology and progression, response to therapeutics, and is a potential disease biomarker. While AD animal models confirm DNA integrity impacts neuronal development, function, and maintenance and human aging studies further implicate a role for GIN in brain deterioration, GIN’s role in AD is not clear. There is a critical need to evaluate AD-specific GIN, particularly as potential precision therapy targets and early biomarkers defining therapeutic windows. Our interdisciplinary research team has AD, aging, genomic instability, cancer, genomics, and data science expertise and is well positioned to undertake these studies. Our long term research goal is to understand the role of GIN in the context of aging for multiple conditions and how GIN further contributes to disease etiology, progression, and treatment. Here, we propose the first steps towards demonstrating utility of our methodology in additional diseases by applying them to publicly available AD human and mouse data and comparing the resulting GIN profiles to cancer data analyses in our parent award. We hypothesize this will determine the extent and type of CIN (Aim 1) and DNAm instability (Aim 2) in AD. Critically, we will demonstrate how generalizable our methods and gained knowledge are, add AD examples and vignettes to the tools we are developing, and compare GINs across diseases (AD and cancers), species (human and mouse), and with respect to sex and age. Additionally, we will generate genotype and DNAm data from 3xTG-AD mouse hippocampus (AD-relevant brain tissue), tibialis anterior muscle (as a sentinel organ), and plasma (as a circulating factor) to investigate GIN as an AD biomarker. Critically, with this supplement we will demonstrate generalizability of the parent award methods and knowledge by expanding our existing non-AD NHGRI award to have an AD focus. This work will also stimulate additional activity and collaborations in AD and related dementias by providing preliminary data for several future grant proposals targeting the role of GIN in aging as a general disease mechanism, in AD pathogenesis, for drug repurposing and shared etiology studies between cancer and AD, and with respect to the utility of GINs as peripheral or circulating biomarkers.