mTOR, Inflammation and Senescence of Hematopoietic Stem Cells

描述(由申请人提供)：组织干细胞的衰老，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解决。虽然人们普遍认为组织干细胞的衰老既有细胞固有的因素，也有环境因素，但环境因素是如何转化为其HSC衰老的，目前尚不清楚。MTOR途径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，在衰老的HSC中，mTOR通路被过度激活，这种激活是导致HSC功能缺陷和HSC衰老的必要条件和充分条件。MTOR激活的潜在原因尚不清楚。在这里，我们计划采用生化、遗传学和免疫学方法来确定衰老HSC中mTOR激活的原因。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，我们证明了用雷帕霉素治疗6周可以使老化的HSC恢复活力。这一结果带来了一个耐人寻味的潜力，可以将我们的基本发现转化为对日益增长的老年人口的临床护理。我们建议的研究有两个具体目标。具体目的1.确定老年小鼠炎症细胞因子产生增加和HSC衰老的根本原因。特定目的II.确定短暂使用小剂量雷帕霉素以恢复衰老的HSC的潜在治疗窗口。这一应用是基于我们在HSC功能和HSC衰老中TSC-mTOR途径以及调控细胞损伤免疫反应的一条新途径方面的几项令人兴奋和创新的研究成果发表在J.Exp。医学，科学信号和科学，在过去的两年。我们提出的研究不仅将阐明HSC衰老的基本机制，而且还将为HSC的治疗复壮提供新的途径。建议的研究完成后，将对临床应用产生即时和长期的影响。 公共卫生相关性：造血干细胞(HSC)的老化是衰老的主要潜在机制，影响免疫系统并增加白血病发病率。MTOR途径已经成为许多细胞类型的环境和营养条件的主要传感器。由于衰老机体表现出较高水平的炎性细胞因子，而且一些炎性细胞因子已被证明激活mTOR途径，我们提出了一个中心假说：衰老机体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)。老年小鼠炎症细胞因子产生增加和HSC衰老的分子机制是什么？(2)短期使用雷帕霉素来恢复衰老的HSC是否有治疗窗口？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，而且将为HSC的治疗复壮提供新的途径。该研究将对临床应用产生直接和长期的影响。

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.