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.

抽象/总结