mTOR, Inflammation and Senescence of Hematopoietic Stem Cells

描述（由申请人提供）：组织干细胞（包括造血干细胞（HSC））的衰老是生物体衰老的主要潜在机制。尽管进行了广泛的分析，但HSC衰老的根本原因在很大程度上仍未得到解决。虽然人们普遍认为细胞内在因素和环境因素都参与了组织干细胞的衰老，但衰老生物体中的环境因素如何转化为HSC的衰老尚不清楚。mTOR通路已经成为许多细胞类型的环境和营养条件的主要传感器。在过去的几年里，我的实验室一直在研究mTOR在HSC功能中的作用。我们的初步数据表明，mTOR通路在老化的HSC中被过度激活，并且这种激活对于引起HSC的功能缺陷以及HSC衰老是必要的且足够的。mTOR激活的根本原因仍不清楚。在这里，我们计划采取生物化学，遗传学和免疫学的方法来确定衰老HSC中mTOR激活的原因。作为我们证明mTOR激活在HSC老化中的重要作用的效果的一部分，我们表明用雷帕霉素治疗六周可以使老化的HSC恢复活力。这一结果提出了一个有趣的潜力，将我们的基本发现转化为日益老龄化的人口的临床护理。我们建议的研究有两个具体目标。 具体目标一。确定老年小鼠炎性细胞因子产生增加和HSC衰老的根本原因。 具体目标二。确定一个潜在的治疗窗口，短暂使用低剂量雷帕霉素，以振兴老化的HSC。 本申请基于我们在HSC功能和HSC衰老中的TSC-mTOR途径中的几条令人兴奋和创新的研究，以及在J. Exp.医学，在过去的两年里，科学信号和科学。我们的研究不仅将阐明HSC衰老的基本机制，而且将为HSC的治疗性复壮提供新的方法。拟定研究的完成将对临床应用产生直接和长期影响。 公共卫生相关性：造血干细胞（HSC）老化是衰老的主要潜在机制，影响免疫系统和增加白血病发病率。mTOR通路已经成为许多细胞类型的环境和营养条件的主要传感器。由于衰老生物体表现出更高水平的炎性细胞因子，并且由于一些炎性细胞因子已显示出激活mTOR途径，我们提出了一个中心假设：衰老生物体中产生的炎性细胞因子通过激活mTOR途径触发HSC衰老。我们将研究：（1）。老年小鼠炎性细胞因子产生增加和HSC衰老的分子机制是什么？(2)短期使用雷帕霉素使衰老的HSC恢复活力是否存在治疗窗口？ 我们提出的研究有可能证明炎症是HSC衰老的根本原因。这不仅将阐明HSC衰老的基本机制，而且为HSC的治疗性复壮提供了新的途径。该研究将在临床应用中产生直接和长期影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Aging of hematopoietic stem cells (HSC) is a major underlying mechanism for aging, affecting the immune system and increased leukemia incidence. The mTOR pathway has emerged as a major sensor for environmental and nutrient conditions of many cell types. Since the aging organism exhibits higher levels of inflammatory cytokines, and since some of the inflammatory cytokines have been shown to activate mTOR pathway, we have formulated a central hypothesis: Inflammatory cytokine produced in the aging organism triggers HSC senescence by activation of mTOR pathway. We will examine: (1). What is the molecular mechanism of elevated inflammatory cytokine production and HSC senescence in the old mice? (2) Is there a therapeutic window for short-term use of rapamycin to rejuvenate aging HSC? Our proposed studies have the potential to demonstrate inflammation as the underlying cause of HSC senescence. This will not only elucidate a fundamental mechanism of HSC aging, but also provide novel approaches for therapeutic rejuvenation of HSC. The study will have both immediate and long term impact in clinical application.