Novel longevity enhancing pathways regulated by mTOR

mTOR 调控的新长寿途径

• 批准号: 10446243
• 负责人: CHRISTIAN SELL
• 金额: $ 39.63万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446243
• 关键词: Aging; Alzheimer' s Disease; CCCTC-binding factor; CDKN2A gene; Cell Aging; Cell Compartmentation; Cells; Clinical; Complex; Data; Development; Disease; Drug usage; EZH2 gene; Elderly; FDA approved; FRAP1 gene; Functional disorder; Genetic Transcription; Goals; Grant; H19 gene; Heart failure; Human; Inflammation; Intervention; Laboratories; Longevity; Maintenance; Mediating; Mediator of activation protein; Metabolic; MicroRNAs; Modeling; Monitor; Mus; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Play; Promoter Regions; RNA; Regulation; Reporter; Research; Role; Signal Transduction; Sirolimus; Somatic Cell; TP53 gene; Testing; Tissues; Untranslated RNA; Work; Zinc Fingers; adult stem cell; age related; cell type; chromatin modification; clinical development; gene repression; healthy aging; immune function; improved; in vivo; individual response; inhibitor; mTOR Inhibitor; mTOR inhibition; member; novel; novel marker; pluripotency; prevent; programs; promoter; response; senescence; side effect; stem cell function; stem cell population; stem cells

ABSTRACT/SUMMARY Inhibitors of the mTOR pathway are among the most promising interventions to target age-related dysfunction, however, there is a critical need to further define the pro longevity effects to facilitate clinical development of mTOR inhibitors. The current proposal will significantly advance this effort providing new targets for intervention and novel markers to monitor individual responses to mTOR inhibition. The overarching goal of this research program is to develop a mechanistic understanding of novel downstream targets of rapamycin, in order to facilitate safer and more effective strategies to promote healthy aging. Cellular senescence occurs in both somatic and stem cell populations and contributes to age-related dysfunction, and our laboratory has shown that mTOR inhibition using rapamycin, can prevent entry into the senescent state. The mTOR pathway also regulates senescence a n d pluripotency in a variety of stem cell populations. The central hypothesis of the application is that mTOR inhibition by rapamycin prevents senescence and enhances pluripotency by increasing the lncRNA H19. The rationale for this hypothesis is our observation that rapamycin increases levels of the non- coding RNA (lncRNA) H19. We find that levels of H19 decrease during senescence and in pluripotent cells. H19 plays a central role during development and differentiation, and maintenance of adult stem cell populations. Rapamycin increases H19 levels, prevents senescence and maintains pluripotency. The results suggest that increasing H19 levels in response to mTOR inhibition may play a dual role, inhibiting senescence while simultaneously increasing pluripotency in adult stem cell populations. The proposed work will provide transformative data regarding a novel mechanism for lifespan extension and improvement of late-life function in multiple tissues.

摘要/总结 mTOR通路的抑制剂是针对年龄相关性疾病的最有希望的干预措施之一。 然而，功能障碍，迫切需要进一步定义长寿效应，以促进临床 开发mTOR抑制剂。目前的建议将大大推动这一努力，提供新的 用于干预的靶点和用于监测个体对mTOR抑制的反应的新标记物。的 这项研究计划的总体目标是发展一个新的下游机制的理解， 雷帕霉素的靶点，以促进更安全，更有效的策略，以促进健康老龄化。 细胞衰老发生在体细胞和干细胞群体中，并有助于与年龄相关的衰老。 功能障碍，我们的实验室已经表明，使用雷帕霉素抑制mTOR可以阻止进入细胞。 衰老状态mTOR通路还调节多种干细胞的衰老和多能性。 人口。本申请的中心假设是雷帕霉素对mTOR的抑制防止了 衰老并通过增加lncRNA H19来增强多能性。这一假设的基本原理是 我们观察到雷帕霉素增加了非编码RNA（lncRNA）H19的水平。我们发现， H19在衰老和多能细胞中减少。H19在发育过程中起着核心作用， 分化和维持成体干细胞群。雷帕霉素增加H19水平，防止 衰老并保持多能性。结果表明，增加H19水平对mTOR的反应， 抑制作用可发挥双重作用，抑制衰老，同时增加成年人多能性 干细胞群体拟议的工作将提供关于一种新机制的变革性数据， 延长寿命和改善多种组织的晚年功能。