Novel longevity enhancing pathways regulated by mTOR

mTOR 调控的新长寿途径

基本信息

批准号：
10358671
负责人：
CHRISTIAN SELL
金额：
$ 31.05万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358671
关键词：
Aging Alzheimer&apos s Disease CDKN2A gene Cell Aging Cell Compartmentation Cells Clinical Complex Data Development Disease Drug usage Elderly Evaluation FDA approved FRAP1 gene Functional disorder Genetic Transcription Goals Grant H19 gene Heart failure Inflammation Intervention Laboratories Longevity Maintenance Mediating Mediator of activation protein Metabolic MicroRNAs Modeling Monitor Mus Nuclear Pathway interactions Pharmaceutical Preparations Phosphotransferases Play Population RNA RNA Stability Regulation Reporter Research Role Signal Transduction Sirolimus Somatic Cell Testing Tissues Untranslated RNA Work adult stem cell age related cell type chromatin modification clinical development gene repression healthy aging immune function improved in vivo individual response inhibitor/antagonist mTOR Inhibitor mTOR inhibition member novel novel marker pluripotency prevent programs promoter response senescence side effect stem cell function stem cell population stem cells

项目摘要

Abstract 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 and 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 noncoding 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.

抽象的 mTOR 通路抑制剂是针对年龄相关功能障碍最有希望的干预措施之一，然而，迫切需要进一步确定延长寿命的效果，以促进临床开发当前的提案将显着推进这项工作，为 mTOR 抑制剂提供新的靶点。监测个体对 mTOR 抑制反应的干预和新标记物。该研究计划旨在对雷帕霉素的新下游靶点形成机制理解，为了促进更安全、更有效的策略来促进健康衰老。体细胞和干细胞群都会导致与年龄相关的功能障碍，我们的实验室已经结果表明，使用雷帕霉素抑制 mTOR，可以阻止 mTOR 途径进入衰老状态。还调节多种干细胞群体的衰老和多能性。应用是雷帕霉素抑制 mTOR 可防止衰老并增强多能性增加 lncRNA H19 这一假设的基本原理是我们观察到雷帕霉素增加。我们发现 H19 的水平在衰老过程中会降低。 H19 多能细胞在发育和分化以及成体的维持过程中发挥着核心作用。雷帕霉素可提高 H19 水平，防止衰老并维持多能性。结果表明，响应 mTOR 抑制而增加 H19 水平可能发挥双重作用，抑制衰老，同时增加成体干细胞群的多能性。这项工作将提供有关延长寿命的新机制的变革性数据改善多种组织的晚年功能。