Investigation of synergism between mTOR and eEF2 kinase pathways

项目主任/首席研究员(最后、第一、中间)：Pi：Alexey G.Ryazanov，博士 摘要 TOR途径在衰老过程中起着重要作用。已经证明，通过治疗 雷帕霉素能延长不同生物的寿命。TOR途径的一个组成部分是 EEF2激酶(EEF2K)，通过磷酸化调节蛋白质合成的全球速度 伸长因子2(EEF2)。TOR的激活导致eEF2K的抑制，这是其机制的一部分 增加蛋白质合成的速度。最近，我们产生了eEF2K基因敲除的小鼠，并发现其 灭活可保护干细胞免受凋亡并延缓衰老。因此，存在着一个悖论：一方面 抑制TOR可以延缓衰老，而抑制TOR可能通过以下途径加速衰老 激活eEF2K。因此，雷帕霉素抑制TOR产生两个相反的信号：抑制TOR TOR途径在延缓衰老的同时激活eEF2K，这可能是为了中和抗衰老 雷帕霉素的衰老作用。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的失活是否可以 与雷帕霉素协同产生抗衰老作用。 PHS 398/2590(06/09版)第1页续格式页

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