Investigation of synergism between mTOR and eEF2 kinase pathways

描述（由申请人提供）：TOR 通路在衰老过程中发挥着重要作用。已证明，雷帕霉素治疗可延长多种生物体的寿命。 TOR 通路的组成部分之一是 eEF2 激酶 (eEF2K)，它通过延伸因子 2 (eEF2) 的磷酸化调节蛋白质合成的总体速率。 TOR 的激活会导致 eEF2K 的抑制，这是增加蛋白质合成速率的机制的一部分。最近，我们培育了 eEF2K 敲除小鼠，发现其失活可以保护干细胞免于凋亡并延缓衰老。由此可见，存在一个悖论：一方面抑制TOR会延缓衰老，另一方面抑制TOR又可能通过激活eEF2K而加速衰老。因此，雷帕霉素抑制TOR会产生两个相反的信号：抑制TOR通路会减缓衰老，同时激活eEF2K，这可能会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 eEF2K 失活是否可以与雷帕霉素协同产生抗衰老作用来检验这一假设。 公共健康相关性：mTOR 介导的营养传感通路和 eEF2K 介导的应激反应通​​路的慢性激活都会导致衰老。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条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.