Investigation of synergism between mTOR and eEF2 kinase pathways

描述（申请人提供）：TOR通路在衰老过程中起重要作用。已经证明，用雷帕霉素治疗可以延长多种生物体的寿命。TOR通路的一个组成部分是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率。TOR的激活导致eEF2K的抑制，这是增加蛋白质合成速率的机制的一部分。最近，我们培育了敲除eEF2K的小鼠，发现其失活可以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延缓衰老，另一方面抑制TOR可能通过激活eEF2K加速衰老。因此，雷帕霉素对TOR的抑制产生了两个相反的信号：抑制TOR通路减缓衰老的同时激活了eEF2K，这可能抵消了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灭活是否能与雷帕霉素协同产生抗衰老作用来验证这一假设。

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.