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

通过 mTOR 抑制逆转动脉老化：AMPK 激活作为 Rapalog

基本信息

批准号：
8726271
负责人：
Anthony John Donato
金额：
$ 22.35万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8726271
关键词：
3-nitrotyrosine Adult Adverse effects Aftercare Age Aging Aminoimidazole Carboxamide Animals Arteries Attenuated Behavior Biological Availability Blood Vessels CCI-779 Cardiovascular Diseases Cause of Death Chronic Clinical Trials Data Development Diet Disease Elderly Electron Spin Resonance Spectroscopy Endothelium Environment Female Functional disorder Gene Proteins Healthcare Human Inflammation Inflammatory Interleukin-6 Laboratories Life Style Longevity Manganese Superoxide Dismutase Mediating Molecular Morbidity - disease rate Mus NADPH Oxidase NF-kappa B Nitric Oxide Organ Oxidative Stress Pathway interactions Pharmacologic Substance Phenotype Physiological Play Prevention Prevention strategy Process Reactive Oxygen Species Ribonucleotides Risk Risk Factors Role Signal Pathway Signal Transduction Sirolimus Societies Superoxides Testing Tissues Tumor Necrosis Factor-alpha United States Vascular Cell Adhesion Molecule-1 Work age related arterial stiffness base care burden dietary supplements endothelial dysfunction feeding genetic manipulation human FRAP1 protein improved in vivo insight mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition male middle age mortality mouse model novel prevent protein expression public health relevance transcription factor vascular inflammation

项目摘要

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.

描述（由申请人提供）：心血管疾病（CVD）是美国死亡的主要原因。衰老是CVD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，是内皮功能降低并增强了大动脉僵硬。最近，已经证明，通过雷帕霉素或遗传操作抑制MTOR信号通路可延长寿命并降低与年龄相关的生理功能障碍。拟议的研究旨在确定（a）MTOR信号是否导致与年龄相关的动脉功能障碍以及（b）饮食中的雷帕霉素治疗和AMPK的激活（推定的“ Rapalog”）是否可以反向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，并且这与与年龄相关的内皮功能障碍和大动脉相关，而大动脉僵硬，已知是氧化应激和炎症的增加所致。此外，用MTOR抑制剂雷帕霉素对旧小鼠的饮食治疗可以扭转这种与年龄相关的动脉表型并改善动脉功能。在本应用中，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/蛋白质表达以及随后对动脉表型和功能的影响中所发挥的作用。此外，我们还将确定AICAR对AMPK的药理激活是否将充当“ Rapalog”，模仿雷帕霉素诱导的MTOR抑制对动脉功能和表型的影响。