Reversing Arterial Aging via mTOR Inhibition: AMPK Activation as a Rapalog

描述（由申请人提供）：心血管疾病（CVD）是美国的主要死亡原因。衰老是心血管疾病发展的主要危险因素。与年龄相关的主要动脉表型被认为是老年人CVD发展的原因，是内皮功能降低和大动脉僵硬度增强。最近，已经证明，通过雷帕霉素或遗传操作抑制mTOR信号通路，可以延长寿命并减少与年龄相关的生理功能障碍。拟议的研究旨在确定（a）增加的mTOR信号传导是否是年龄相关的动脉功能障碍的原因，以及（B）饮食雷帕霉素治疗和AMPK（一种假定的“雷帕霉素”）的激活是否可以逆转年龄相关的动脉功能障碍。我们的实验室已经进行了初步研究，表明mTOR的动脉激活随着年龄的增长而增加，并且这伴随着年龄相关的内皮功能障碍和已知由氧化应激和炎症增加引起的大动脉硬化。此外，用mTOR抑制剂雷帕霉素对老年小鼠进行饮食治疗可以逆转这种年龄相关的动脉表型并改善动脉功能。在本申请中，通过利用饮食雷帕霉素治疗，我们将直接评估mTOR在调节转录因子活性和下游基因/蛋白质表达中的作用以及随后对动脉表型和功能的影响。此外，我们将确定AICAR对AMPK的药理学激活是否会作为一种“雷帕霉素”，模拟雷帕霉素诱导的mTOR抑制对动脉功能和表型的影响。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the United States. Aging is the major risk factor for development of CVD. The major age-related arterial phenotypes, which are thought to be responsible for the development of CVD in older adults, are reduced endothelial function and enhanced large artery stiffness. Recently, it has been demonstrated that inhibition of the mTOR signaling pathway, via rapamycin or genetic manipulation, extends lifespan and reduces age-related physiological dysfunction. The proposed studies aim to determine (a) if increased mTOR signaling is responsible for age-related arterial dysfunction and (b) whether dietary rapamycin treatment and activation of AMPK, a putative "rapalog", can reverse age-related arterial dysfunction. Our laboratory has performed preliminary studies suggesting that arterial activation of mTOR is increased with advancing age and that this is concomitant with age-associated endothelial dysfunction and large artery stiffening known to result from increases in oxidative stress and inflammation. Furthermore, dietary treatment of old mice with mTOR inhibitor, rapamycin, can reverse this age-associated arterial phenotype and improve arterial function. In the present application, by utilizing dietary rapamycin treatment, we will directly assess the role that mTOR plays in modulating transcription factor activity and downstream gene/protein expression and the subsequent effects on arterial phenotype and function. In addition, we will determine if pharmacological activation of AMPK by AICAR will act as a "rapalog," mimicking the effects of rapamycin-induced mTOR inhibition on arterial function and phenotype.