Investigation of synergism between mTOR and eEF2 kinase pathways

mTOR 和 eEF2 激酶通路之间的协同作用研究

基本信息

批准号：
8445866
负责人：
ALEXEY G. RYAZANOV
金额：
$ 23.72万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445866
关键词：
Ablation Affect Aging Aging-Related Process Apoptosis Apoptotic Autophagocytosis Cells Cellular Stress Chronic DNA Damage Doctor of Philosophy Embryo Fibroblasts Future Genetic Glutamic Acid Growth Hematopoietic Hematopoietic System Hematopoietic stem cells Investigation Knock-out Knockout Mice Lead Life Life Support Care Longevity Mediating Metabolism Mitochondria Molecular Mus Organism Oxidative Stress Pathway interactions Peptide Elongation Factor 2 Pharmaceutical Preparations Phenocopy Phosphorylation Phosphotransferases Play Principal Investigator Process Production Protein Biosynthesis Proteins Radio Regulation Research Resistance Respiration Ribosomal Protein S6 Kinase Role Signal Transduction Sirolimus Stem cells Stress Stress Response Signaling Testing Therapeutic Time Tissues Translations Work age effect aged anti aging biological adaptation to stress calmodulin-dependent protein kinase III cell growth detection of nutrient human FRAP1 protein in vitro activity knockout animal mTOR Inhibitor mimetics mouse model mutant novel practical application prevent programs protein misfolding reconstitution response stem synergism theories

项目摘要

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.

描述（由申请人提供）：TOR途径在衰老中起重要作用。已经证明，用雷帕霉素的治疗导致多种生物的寿命延长。 TOR途径的组成部分之一是EEF2激酶（EEF2K），它通过伸长因子2（EEF2）的磷酸化来调节蛋白质合成的全局速率。 TOR的激活导致抑制EEF2K，这是增加蛋白质合成速率的机制的一部分。最近，我们生成了用EEF2K敲除的小鼠，发现其灭活可保护干细胞免受凋亡和衰老的衰老。因此，存在一个悖论：一方面，TOR的抑制作用会减慢衰老，另一方面，TOR的抑制可能会通过激活EEF2K加速衰老。因此，雷帕霉素对TOR的抑制作用会产生两个相反的信号：抑制Tor途径会减慢衰老，同时激活EEF2K，这可能抵消了雷帕霉素的抗老化作用。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作用，从而产生抗衰老作用来检验这一假设。公共卫生相关性：MTOR介导的营养感应途径的长期激活和EEF2K介导的应力反应途径都会导致衰老。该提案旨在探索MTOR和EEF2K途径之间的功能和分子相互关系，并确定同时抑制这两种途径是否会对减慢衰老过程的降低产生协同作用。这项研究的结果将对理解衰老的机制具有重要意义，并可能在将来带来治疗机会。