Genetic variant-based drug discovery targeting conserved pathways of aging

摘要（总体） 衰老是大多数常见慢性人类疾病的最大风险因素，也是发展的逻辑目标。 采取干预措施，预防、减轻或扭转与年龄有关的多种疾病。在过去的二十年里，基因 针对保守的生长和代谢途径的药物干预一直导致 大幅度延长线虫、苍蝇和 小鼠必须将模式生物获得的结果扩展到老年人。在此提出的 更新我们的U19项目“基于遗传变异的药物发现靶向衰老的保守途径”，我们 建议继续使用人类百岁老人来识别遗传变异，作为开发药物的目标， 改善人体健康衰老。在第一个资助期间，我们确定了罕见的变异和长寿途径 在我们的百岁老人队列中，包括IGF-1 R，SIRT 6和ATM的编码变体，以及功能性非编码变体。 FOXO 3A、SIRT 6和IKK/NF-κ B B通路的组分、RelA/p65、NF κ B 1/p50和NF κ B 1a中的变体 （I）B乙）。在确定了利用人类百岁老人的遗传学来鉴定基因的可行性之后， 作为促进人类健康的潜在药物靶点的候选途径， 应用程序将通过我们自己的全外显子组分析扩展程序，大大扩展 队列和其他百岁老人队列，进一步的基因功能化，使用新的小鼠模型， 加速老化，以验证罕见变异和途径在健康长寿中的作用， 我们筛选候选干预措施的管道。为了实现这些目标，我们提出了一个跨学科的 方法，充分利用细胞基因组学，高通量功能筛选，干细胞， 细胞生物学、小鼠和人类遗传学以及药物筛选。此更新申请包括四个 项目项目1：人类极端长寿的遗传分析（Zhang、Dong和Vijg）;项目2：鉴定 功能性遗传罕见变异（Suh和Yu），项目3： 小鼠衰老模型（Niedernhofer）和项目4：针对已确定的 变异和途径（罗宾斯和Gorbunova）。还有一个数据研究资源核心 集成和共享（核心B; Zhang和Dong）以及管理核心（核心A; Vijg，Robins和 Barzilai）。我们希望继续和扩大使用人类百岁老人队列将使我们能够 获得更详细的遗传信息，这些信息对于确定药物开发的目标至关重要， 例如，通过增加对阿尔茨海默病病理学的适应力，

ABSTRACT (OVERALL) Aging is the greatest risk factor for most common chronic human diseases and a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. It is imperative to extend the results obtained with model organisms to aging humans. In this proposed renewal of our U19 project “Genetic variant-based drug discovery targeting conserved pathways of aging” we propose to continue using human centenarians to identify genetic variants as targets for developing drugs that improve human healthy aging. During the first funding period, we identified rare variants and longevity pathways in our centenarian cohort including coding variants in IGF-1R, SIRT6, and ATM, and functional non-coding variants in FOXO3A, SIRT6 and components of the IKK/NF-B pathway, RelA/p65, NFKB1/p50 and NFKB1a (IB). Having established the feasibility of using the genetics of human centenarians to identify genes and pathways as candidates for potential drug targets for promoting human healthspan, the focus of this renewal application will be to expand the program through whole exome analysis of our own, significantly expanded cohort and other centenarian cohorts, further gene functionalization, the use of novel mouse models of accelerated aging to validate the role of the rare variants and pathways in healthy longevity, and expansion of our pipeline of screening for candidate interventions. To accomplish these goals, we propose an interdisciplinary approach, making full use of the latest advances in cellular genomics, high-throughput functional screening, stem cell biology, mouse and human genetics and drug screening. This renewal application is comprised of four projects. Project 1: Genetic analysis of extreme human longevity (Zhang, Dong, and Vijg); Project 2: Identification of functional genetic rare variants (Suh and Yu), Project 3: Validation and characterization of rare variants in mouse models of aging (Niedernhofer) and Project 4: Development of novel therapeutics targeting the identified variants and pathways (Robbins and Gorbunova). There is also one Research Resource Core for Data Integration and Sharing (Core B; Zhang and Dong) as well as an Administrative Core (Core A; Vijg, Robins and Barzilai). We expect that the continued and expanded use of the human centenarian cohorts will allow us to obtain more detailed genetic information critical for identifying targets for the development of drugs for extending human healthspan, for example, by increasing resilience to Alzheimer’s Disease pathology.