mTOR, Inflammation and Senescence of Hematopoietic Stem Cells

摘要包括造血干细胞在内的组织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，但根本原因是 HSC的衰老在很大程度上仍未得到解决。尽管人们普遍认为这两个细胞 内在和环境因素参与了组织干细胞的衰老， 衰老生物体中的环境因素转化为其HSC衰老的机制尚不清楚。这个 MTOR途径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 HSC.我们的初步数据显示，mTOR通路在衰老的HSC中过度激活，并 这种激活既是必要的，也是充分的，从而导致HSC以及HSC的功能缺陷 衰老。MTOR激活的潜在原因尚不清楚。在这里，我们计划采取 生化、遗传学和免疫学方法确定衰老过程中mTOR激活的原因 HSC.作为我们展示mTOR激活在HSC老化中的重要作用的效果的一部分，我们展示了 用雷帕霉素进行六周的治疗可以使老化的HSC恢复活力。这一结果引发了一个耐人寻味的问题 将我们的基本发现转化为对日益老龄化人口的临床护理的潜力。我们的 拟议的研究详细说明了两个具体目标。 具体目标一.确定炎性细胞因子产生增加的根本原因和 老龄小鼠肝星状细胞衰老。 具体目标II.确定短暂使用低剂量药物的潜在治疗窗口 雷帕霉素使衰老的HSC恢复活力。 这一应用是基于我们在TSC-mTOR方面的几项令人兴奋和创新的研究 肝星状细胞功能和衰老途径以及免疫调节新途径 对细胞损伤的反应发表在J.Exp。医学，科学信号和科学，在过去的两年。我们的 所提出的研究不仅将阐明HSC衰老的基本机制，而且还将为HSC衰老提供新的 肝星状细胞治疗复壮的方法。建议的研究完成后，将同时具备这两项功能 对临床应用的即刻和长期影响。

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.