mTOR, Inflammation and Senescence of Hematopoietic Stem Cells

摘要组织干细胞包括造血干细胞的衰老是一个重要的生物学过程。 生物体衰老的主要潜在机制。尽管进行了广泛的分析， HSC衰老的机制仍在很大程度上尚未解决。尽管通常认为两种细胞 内源性和环境因素参与组织干细胞的衰老， 衰老生物体中的环境因素转化为HSC的衰老尚不清楚。的 mTOR通路已经成为许多细胞环境和营养条件的主要传感器 类型在过去的几年里，我的实验室一直在研究mTOR在以下功能中的作用： HSC。我们的初步数据表明，mTOR通路在衰老的HSC中被过度激活， 这种激活是必需的，并且足以引起HSC的功能缺陷， 衰老mTOR激活的根本原因仍然未知。在这里，我们计划采取 生物化学、遗传学和免疫学方法来鉴定衰老中mTOR激活的原因 HSC。作为我们证明mTOR激活在HSC老化中的重要作用的一部分，我们发现 用雷帕霉素治疗六周可以使老化的HSC恢复活力。这一结果引发了一个有趣的 将我们的基本发现转化为日益老龄化的人口的临床护理的潜力。我们 拟议的研究有两个具体目标。 具体目标一。为了确定炎症细胞因子产生增加的根本原因， 老年小鼠肝星状细胞衰老。 具体目标二。确定短暂使用低剂量的潜在治疗窗 雷帕霉素以使老化的HSC恢复活力。 该应用基于我们在TSC-mTOR中的几项令人兴奋和创新的研究 在HSC功能和HSC衰老中的作用途径，以及调节免疫的新途径， 对细胞损伤的反应发表在J. Exp.医学，在过去的两年里，科学信号和科学。我们 这些研究不仅将阐明HSC衰老的基本机制，而且还将提供新的 HSC的治疗性再生的方法。拟议研究完成后， 对临床应用有直接和长期影响。

Abstract The senescence of tissue stem cells, including that of hematopoietic stem cells (HSC), is a major underlying mechanism for aging of an organism. Despite extensive analysis, the underlying cause for senescence of HSC remains largely unresolved. Although it is generally accepted that both cell intrinsic and environmental factors are involved in senescence of tissue stem cells, how the environmental factor in the aging organisms translates into senescence of their HSC is unclear. The mTOR pathway has emerged as a major sensor for environmental and nutrient conditions of many cell types. In the past several years, my laboratory has been investigating the role of mTOR in the function of HSC. Our preliminary data demonstrated that the mTOR pathway is over-activated in the aging HSC and that such activation is both necessary and sufficient to cause functional defects of HSC, as well as HSC senescence. The underlying cause of mTOR activation remained unknown. Here we plan to take biochemical, genetic and immunological approaches to identify the cause of mTOR activation in aging HSC. As part of our effect to demonstrate essential role for mTOR activation in HSC aging, we showed that a six-week treatment with rapamycin can rejuvenate the aging HSC. This result raised an intriguing potential to translate our fundamental discovery to clinical care of the increasingly older population. Our proposed studies are detailed in two specific aims. Specific Aim I. To identify the root cause of enhanced inflammatory cytokine production and HSC senescence in the old mice. Specific Aim II. To identify a potential therapeutic window for transient use of low dose rapamycin to rejuvenate aging HSC. This application is based on our several lines of exciting and innovative studies in TSC-mTOR pathway in HSC function and in HSC senescence, as well as a novel pathway in regulating immune response to cell injury published in J. Exp. Med., Science Signaling and Science in past two years. Our proposed studies will not only elucidate a fundamental mechanism of HSC aging, but also provide novel approaches for therapeutic rejuvenation of HSC. The completion of the proposed study will have both immediate and long term impact for clinical application.