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.

有关AD/ADRD的补充资金请求的项目摘要 阿尔茨海默氏病（AD）是痴呆症的最常见形式，代表三分之二的痴呆病例。 虽然AD是100年前首次描述的，但该疾病的病因仍然在很大程度上尚不清楚。 尽管AD在神经元，跨大脑和整个整个神经元内的影响有明显的相关性 AD患者的身体，在这些情况下的因果关系之间的关系尚不清楚。一个 需要全面的系统处理来了解广告引起的全部影响 相关过程。完整的系统分析可以在模型遗传系统中进行最强大的进行。 线虫秀丽隐杆线虫是研究衰老遗传学的首要系统，而父母则是父母项目 该补充剂的目的是直接旨在将该模型转移到一个完整的基因和细胞系统中 分析框架。但是，使用秀丽隐杆线虫作为AD的模型有两个主要障碍。 首先，线虫在一生中似乎并没有获得广告的类似物，但他们没有 固有地表达了一些被认为介导AD发作的蛋白质。第二，还有更多 有用的是，目前尚无验证的范式来研究神经元的维护 秀丽隐杆线虫的健康。在这里，我们以系统遗传学的实验范围和框架为基础 我们首次开发的衰老，产生了一种男性特定的神经元健康模型 在整个生命周期中，都可以理解和可验证的对适当功能的期望 个人。具体而言，我们将（1）构建与广告相关的蛋白质敲入和敲除系统 用作我们正在生成的数十个组织特异性表达线中的功能探针 （2）使用高精度显微镜在我们的系统衰老管道中测试这些结构 成像和完全新颖的全生物单细胞转录分析。因为我们是 在为父母项目建立遗传资源的早期，这种补充剂创造了独特的 有机会利用我们目前的努力，以提供对广告相关综合症的广泛见解。 生物系统水平分辨率。