Novel longevity enhancing pathways regulated by mTOR

mTOR 调控的新长寿途径

基本信息

批准号：
10649541
负责人：
CHRISTIAN SELL
金额：
$ 41.39万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
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/10649541
关键词：
Aging Alzheimer&apos s Disease Breeding CCCTC-binding factor CDKN2A gene Cell Aging Cell Compartmentation Cells Clinical Complex Cytoplasm Data Development Disease Drug usage EZH2 gene Elderly FDA approved FRAP1 gene Family Functional disorder Genetic Transcription Goals Grant H19 gene Heart failure Human Inflammation Intervention Laboratories Longevity Maintenance Mediating Mediator 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 tissue stem cells

项目摘要

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 通路抑制剂是针对年龄相关的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 mTOR抑制剂的开发。当前的提案将显着推进这项工作，提供新的干预目标和监测个体对 mTOR 抑制反应的新标记物。这该研究计划的总体目标是对新型下游产生机械性的理解雷帕霉素的目标，以促进更安全、更有效的策略来促进健康老龄化。细胞衰老发生在体细胞和干细胞群中，并导致与年龄相关的衰老我们的实验室已经证明，使用雷帕霉素抑制 mTOR 可以阻止进入衰老状态。 mTOR 通路还调节多种干细胞的衰老和多能性人口。该申请的中心假设是雷帕霉素抑制 mTOR 可以防止通过增加 lncRNA H19 来抑制衰老并增强多能性。这个假设的基本原理是我们观察到雷帕霉素会增加非编码 RNA (lncRNA) H19 的水平。我们发现水平 H19 在衰老过程中和多能细胞中减少。 H19在发展和发展过程中发挥着核心作用成体干细胞群的分化和维持。雷帕霉素可增加 H19 水平，预防衰老并保持多能性。结果表明，增加 H19 水平以响应 mTOR 抑制可能发挥双重作用，抑制衰老，同时增加成人的多能性干细胞群。拟议的工作将提供有关新机制的变革性数据延长寿命并改善多种组织的晚年功能。