Investigation of synergism between mTOR and eEF2 kinase pathways

项目负责人/主要研究者（最后，第一，中间）：PI：Alexey G. Ryazanov博士 摘要 TOR通路在衰老中起着重要作用。已经证明， 雷帕霉素导致多种生物体的寿命延长。TOR通路的组成部分之一是 eEF 2激酶（eEF 2K）通过磷酸化 延伸因子2（eEF 2）。TOR的激活导致eEF 2K的抑制，作为以下机制的一部分： 增加蛋白质合成的速率。最近，我们产生了敲除eEF 2K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可以减缓衰老，另一方面，抑制TOR可以通过以下途径加速衰老： eEF 2K的激活。因此，雷帕霉素对TOR的抑制导致两个相反的信号： TOR通路减缓衰老，同时激活eEF 2K，这可能会抵消抗- 雷帕霉素的衰老效应。因此，我们假设同时抑制TOR和eEF 2K可以增加细胞的增殖。 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。 PHS 398/2590（Rev. 06/09）第1页

Program Director/Principal Investigator (Last, First, Middle): PI: Alexey G. Ryazanov, Ph.D. Abstract 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. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page