Investigation of synergism between mTOR and eEF2 kinase pathways

描述(申请人提供)：TOR途径在衰老过程中起着重要作用。已有研究表明，雷帕霉素治疗可延长多种生物的寿命。TOR途径的组成部分之一是eEF2激酶(EEF2K)，它通过磷酸化延伸因子2(EEF2)来调节蛋白质合成的整体速度。TOR的激活导致eEF2K的抑制，这是增加蛋白质合成速度的机制的一部分。最近，我们产生了eEF2K基因敲除的小鼠，发现它的失活可以保护干细胞免受凋亡和延缓衰老。因此，存在一个悖论：一方面，抑制TOR可以延缓衰老，另一方面，抑制TOR可能通过激活eEF2K来加速衰老。因此，雷帕霉素抑制TOR产生两个相反的信号：抑制TOR途径延缓衰老，同时激活eEF2K，这可能抵消雷帕霉素的抗衰老作用。因此，我们假设同时抑制TOR和eEF2K会增加TOR抑制衰老的效果。我们将通过确定eEF2K的失活是否可以与雷帕霉素在产生抗衰老效应方面协同作用来检验这一假设。 公共卫生相关性：mTOR介导的营养感知通路的慢性激活和eEF2K介导的应激反应通路都与衰老有关。本研究旨在探讨mTOR和eEF2K通路之间的功能和分子相互关系，并确定同时抑制这两个通路是否能在延缓衰老过程中起到协同作用。这项研究的结果将对了解衰老的机制具有重要意义，并可能在未来带来治疗机会。

DESCRIPTION (provided by applicant): The TOR pathway plays an important role in aging. It has been demonstrated that treatment with rapamycin leads to prolongation of life span in diverse organisms. One of the components of TOR pathway is eEF2 kinase (eEF2K) which regulates the global rate of protein synthesis through phosphorylation of elongation factor 2 (eEF2). Activation of TOR results in the inhibition of eEF2K as a part of the mechanism that increases the rate of protein synthesis. Recently, we generated mice with knockout of eEF2K and found that its inactivation protects stem cells from apoptosis and retards aging. Thus, there exists a paradox: on one hand inhibition of TOR slows down aging, on the other hand inhibition of TOR may accelerate aging through activation of eEF2K. Therefore, the inhibition of TOR by rapamycin results in two opposite signals: inhibition of the TOR pathway slows down aging and at the same time activates eEF2K, which may counteract the anti- aging effect of rapamycin. Thus, we hypothesize that simultaneous inhibition of TOR and eEF2K increases the effect of TOR inhibition on aging. We will test this hypothesis by determining whether inactivation of eEF2K can synergize with rapamycin in producing an anti-aging effect. PUBLIC HEALTH RELEVANCE: Chronic activation of nutrient sensing pathway mediated by mTOR and the stress response pathway mediated by eEF2K both contribute to aging. This proposal seeks to explore the functional and molecular interrelationship between the mTOR and eEF2K pathways and to determine whether the simultaneous inhibition of these two pathways can have a synergistic effect on slowing down aging processes. The results of this study will have important implication for understanding the mechanisms of aging and may potentially result in therapeutic opportunities in the future.