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

整合多维基因组数据以发现临床相关的预测模型-阿尔茨海默氏症补充品

基本信息

批准号：
10286414
负责人：
Brittany Nicole Lasseigne
金额：
$ 21.4万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2021-04-12 至 2023-03-31
项目状态：
已结题

项目摘要

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.

基因组不稳定 (GIN) 是衰老的主要标志，也是已知的最大风险因素因为对于 GIN 的哪种衡量标准最重要，目前还没有达成共识。生物学和临床相关，在我们的母项目中，我们正在测试 GIN 指标并开发工具我们的方法旨在通过技术、平台和方法来重复评估 GIN。与疾病无关，因此也适用于 AD。到目前为止，我们的重点是染色体。不稳定性（CIN、染色体数量和结构改变；例如断点总数、碱基百分比拷贝数变异、总功能非整倍性等）和 DNA 甲基化不稳定性（DNAm，例如， CpG 岛甲基化表型；CIMP、启动子甲基化广泛改变、甲基化密度在癌症中，我们和其他人已经证明 GIN 与疾病病因学和相关性有关。虽然 AD 动物模型证实 DNA 完整性进一步影响神经发育、功能和维护以及人类衰老研究尽管表明 GIN 在大脑退化中发挥作用，但 GIN 在 AD 中的作用尚不清楚，因此迫切需要进行评估。 AD 特异性 GIN，特别是作为潜在的精准治疗靶点和定义治疗的早期生物标志物我们的跨学科研究团队拥有 AD、衰老、基因组不稳定性、癌症、基因组学和数据。我们的长期研究目标是：了解 GIN 在多种衰老情况下的作用以及 GIN 如何进一步促进在此，我们提出了证明其效用的第一步。我们在其他疾病中的方法，将其应用于公开的 AD 人类和小鼠数据，以及我们勇敢地将所得的 GIN 概况与我们的家长奖中的癌症数据分析进行了比较。确定 AD 中 CIN（目标 1）和 DNAm 不稳定性（目标 2）的程度和类型。展示我们的方法和获得的知识的通用性，添加 AD 示例和小插图我们正在开发的工具，并比较不同疾病（AD 和癌症）、物种（人类和小鼠），此外，我们还将生成基因型和 DNAm 数据。 3xTG-AD 小鼠海马体（AD 相关脑组织）、胫骨前肌（作为前哨器官）和至关重要的是，通过这种补充剂，我们将研究 GIN 作为 AD 生物标志物。通过扩展我们现有的非 AD 来展示家长奖励方法和知识的普遍性 NHGRI 授予 AD 重点这项工作也将刺激 AD 领域的更多活动和合作。和相关痴呆症，为未来几项针对 GIN 作用的拨款提案提供初步数据衰老作为一般疾病机制、AD 发病机制、药物再利用和共同病因学癌症和 AD 之间的研究，以及 GIN 作为外周或循环生物标志物的用途的研究。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-read RNA sequencing identifies region- and sex-specific C57BL/6J mouse brain mRNA isoform expression and usage.

长读长 RNA 测序可识别区域和性别特异性 C57BL/6J 小鼠大脑 mRNA 异构体的表达和使用。

DOI：
发表时间：
2024-01-11
期刊：
影响因子：
0
作者：
Jones, Emma F;Howton, Timothy C;Flanary, Victoria L;Clark, Amanda D;Lasseigne, Brittany N
通讯作者：
Lasseigne, Brittany N

Nucleic acid liquid biopsies in Alzheimer's disease: current state, challenges, and opportunities.

阿尔茨海默病的核酸液体活检：现状、挑战和机遇。

DOI：
发表时间：
2022-04
期刊：
影响因子：
4
作者：
Soelter, Tabea M;Whitlock, Jordan H;Williams, Avery S;Hardigan, Andrew A;Lasseigne, Brittany N
通讯作者：
Lasseigne, Brittany N

Evaluating cancer cell line and patient-derived xenograft recapitulation of tumor and non-diseased tissue gene expression profiles in silico.

评估癌细胞系和患者来源的异种移植物在计算机中再现肿瘤和非患病组织基因表达谱。