Administrative Supplement: Systems variation underlying the genetics of aging

行政补充：衰老遗传学背后的系统变异

• 批准号: 9719249
• 负责人: Hang Lu
• 金额: $ 22.49万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9719249
• 关键词: Administrative Supplement; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Brain; Caenorhabditis elegans; Cells; Complex; Dementia; Disease; Etiology; Funding; Future; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic study; Health; Individual; Intervention; Knock-in; Maintenance; Mediating; Modeling; Nematoda; Neurons; Patients; Process; Proteins; Resolution; Syndrome; System; Systems Analysis; Testing; Time; Tissues; Variant; Whole Organism; Work; analog; cost; drug development; expectation; genetic approach; genetic resource; healthy aging; insight; knock-down; male; microscopic imaging; novel; parent project; relating to nervous system; response

Project summary of the supplemental funding request in reference to AD/ADRD Alzheimer's Disease (AD) is the most common form of dementia, representing two thirds of dementia cases. While AD was first described over 100 years ago, the etiology for the disease is still largely unknown. Although there are clear correlates of the impacts of AD within neurons, across the brain, and throughout the bodies of AD patients, the relationship between cause and effect in these cases is still unclear. A comprehensive systems-approach is needed to understand the full cascade of influences induced by AD related processes. Full systems analyses can be most powerfully conducted within a model genetic system. The nematode C. elegans is the premiere system for studying the genetics of aging, and the parent project of this supplement is directly aimed at moving this model into a full gene-by-gene and cell-by-cell systems analysis framework. However, there are two main barriers for using C. elegans as a model for AD. First, nematodes do not appear to acquire an analog of AD during their lifetimes and they do not inherently express some of the proteins thought to mediate the onset of AD. Second, and more perniciously, there is currently no well-verified paradigm for looking at the maintenance of neuronal health in C. elegans. Here we build upon the experimental scope and framework of the systems genetics of aging that we are developing by, for the first time, generating a male-specific model of neuronal health that has understandable and verifiable expectations of proper function throughout the lifetime of an individual. Specifically, we will (1) build AD-related protein knock-in and knock-down systems to be used as functional probes in the dozens of tissue-specific expression lines that we are generating, and (2) test those constructs in our systems-aging pipeline using both high-precision microscopic imaging and a completely novel whole-organism single-cell transcriptional analysis. Because we are still early in building the genetic resources for the parent project, this supplement creates a unique opportunity to leverage our current efforts to provide broader insights into AD related syndromes at whole- organism systems level resolution.

AD/ADRD 补充资金申请的项目摘要 阿尔茨海默病 (AD) 是最常见的痴呆症，占痴呆症病例的三分之二。 尽管 AD 在 100 多年前首次被描述，但该疾病的病因仍然很大程度上未知。 尽管AD对神经元、整个大脑和整个身体的影响存在明显的相关性 AD患者的身体中，这些病例之间的因果关系仍不清楚。一个 需要全面的系统方法来了解 AD 引起的一系列影响 相关流程。完整的系统分析可以在模型遗传系统中进行最有力的分析。 线虫秀丽隐杆线虫是研究衰老遗传学的首要系统，其父项目 该补充的直接目的是将该模型转移到完整的逐个基因和逐个细胞系统中 分析框架。然而，使用线虫作为 AD 模型存在两个主要障碍。 首先，线虫在其一生中似乎并没有获得 AD 的类似物，而且它们也没有 固有地表达一些被认为介导 AD 发作的蛋白质。第二，还有更多 有害的是，目前还没有经过充分验证的范例来研究神经元的维持 线虫的健康。在这里，我们建立在系统遗传学的实验范围和框架之上 我们正在开发的衰老模型，首次生成男性特有的神经元健康模型 在整个生命周期中对正常功能具有可理解和可验证的期望 个人。具体来说，我们将（1）构建AD相关蛋白敲入和敲低系统 用作我们正在生成的数十种组织特异性表达系的功能探针， (2) 使用高精度显微镜在我们的系统老化管道中测试这些结构 成像和全新的全生物体单细胞转录分析。因为我们是 仍处于为父项目构建遗传资源的早期阶段，该补充品创造了独特的 有机会利用我们目前的努力，从整体上提供对 AD 相关综合征更广泛的见解- 有机体系统级别的分辨率。