Administrative Supplement: Systems variation underlying the genetics of aging

关于AD/ADRD的补充资金申请的项目摘要 阿尔茨海默病(AD)是最常见的痴呆症形式，占痴呆症病例的三分之二。 虽然AD是在100多年前首次被描述的，但这种疾病的病因在很大程度上仍然不清楚。 尽管阿尔茨海默病在神经元、整个大脑和整个大脑中的影响有明显的相关性 对于AD患者的身体，这些病例的因果关系尚不清楚。一个 全面的系统-需要采用方法来了解AD引起的影响的全部级联 相关流程。完整的系统分析可以在一个模型遗传系统内进行得最有力。 线虫线虫是研究衰老遗传学的首选系统，也是父母项目 这一补充的直接目的是将这个模型转移到一个完整的逐基因和逐细胞系统中。 分析框架。然而，使用线虫作为AD的模型有两个主要障碍。 首先，线虫在它们的一生中似乎不会获得AD的类似物，它们也不会 固有地表达一些被认为参与阿尔茨海默病发病的蛋白质。其次，还有更多 有害的是，目前还没有得到充分验证的范例来观察神经元的维持 线虫的健康。这里我们建立在系统遗传学的实验范围和框架之上。 我们第一次通过产生一种男性特有的神经元健康模型来发展衰老 具有可理解和可验证的期望，期望在整个生命周期内正常运行 个人的。具体地说，我们将(1)建立与AD相关的蛋白质敲入和敲除系统，以 在我们正在产生的几十个组织特异性表达系中用作功能探针， 和(2)在我们的系统老化管道中使用高精度显微镜 成像和一种全新的整体单细胞转录分析。因为我们是 还在为母项目构建遗传资源的早期阶段，这一补充创造了一个独特的 有机会利用我们目前的努力，从整体上提供对AD相关综合征的更广泛见解- 有机体系统级别的分辨率。

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.