Investigation of synergism between mTOR and eEF2 kinase pathways

描述（由申请人提供）：TOR通路在衰老中起着重要作用。已经证明，用雷帕霉素治疗导致多种生物体的寿命延长。TOR通路的组分之一是eEF 2激酶（eEF 2K），其通过延伸因子2（eEF 2）的磷酸化来调节蛋白质合成的总体速率。TOR的激活导致eEF 2K的抑制，作为增加蛋白质合成速率的机制的一部分。最近，我们产生了敲除eEF2K的小鼠，发现其失活保护干细胞免于凋亡并延缓衰老。因此，存在一个悖论：一方面抑制TOR减缓衰老，另一方面抑制TOR可能通过激活eEF 2K加速衰老。因此，雷帕霉素对TOR的抑制导致两种相反的信号：抑制TOR通路减缓衰老，同时激活eEF 2K，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抑制对衰老的影响。我们将通过确定eEF 2K的失活是否可以与雷帕霉素协同产生抗衰老作用来测试这一假设。 公共卫生相关性：由mTOR介导的营养感受途径和由eEF2K介导的应激反应途径的慢性激活均有助于衰老。该提案旨在探索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种通路是否可以对减缓衰老过程产生协同作用。这项研究的结果将对理解衰老机制具有重要意义，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.