Administrative Supplement: Systems variation underlying the genetics of aging

关于AD/ADRD补充资金申请的项目摘要 阿尔茨海默病（AD）是最常见的痴呆形式，占痴呆病例的三分之二。 虽然AD在100多年前首次被描述，但该疾病的病因在很大程度上仍然未知。 虽然AD在神经元内、整个大脑和整个大脑中的影响有明显的相关性， 虽然AD患者的身体，在这些情况下的因果关系仍然不清楚。一 需要一个全面的系统方法来理解AD引起的全部级联影响 相关过程。全系统分析可以在一个模型遗传系统中最有力地进行。 线虫C. elegans是研究衰老遗传学的首要系统， 这种补充剂的直接目的是将这种模型转移到一个完整的基因和细胞系统中 分析框架。然而，使用C有两个主要障碍。elegans作为AD的模型。 首先，线虫在其一生中似乎不会获得AD的类似物， 固有地表达一些被认为介导AD发作的蛋白质。第二，更多 有害的是，目前还没有经过充分验证的范式来观察神经元的维持， 健康C。优雅在这里，我们建立在系统遗传学的实验范围和框架 我们首次通过生成男性特定的神经元健康模型来开发衰老模型 在整个生命周期内对正常功能具有可理解和可验证的期望， 单独的.具体来说，我们将（1）建立AD相关蛋白敲入和敲低系统， 作为功能性探针，用于我们正在产生的几十种组织特异性表达系， 和（2）测试这些结构在我们的系统老化管道使用高精度显微镜和 成像和一种全新的全生物体单细胞转录分析。因为我们是 在为母项目建立遗传资源的早期阶段，这种补充创造了一种独特的 有机会利用我们目前的努力，提供更广泛的了解AD相关综合征的整体- 有机体系统级分辨率。

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.