The in vivo regulation of glucose homeostasis and lifespan by mTORC2

描述（由申请方提供）：哺乳动物雷帕霉素靶蛋白（mTOR）信号通路是一种高度保守的通路，可调节生长和代谢，以响应营养素的可用性。mTOR信号传导被雷帕霉素抑制，雷帕霉素是一种FDA批准的化合物，广泛用于移植手术中作为免疫抑制剂，以及用于治疗癌症的临床试验。用雷帕霉素治疗延长了许多模型生物体（包括小鼠）的寿命，并且有益于治疗小鼠模型中的衰老疾病（包括阿尔茨海默病）。 用雷帕霉素治疗和抑制mTOR复合物1（mTORC 1）被提出通过类似于热量限制（CR）饮食的机制来促进长寿，其中热量摄入减少， 保持充足的营养。然而，我们发现雷帕霉素也抑制mTOR复合物2（mTORC 2），破坏葡萄糖稳态并增加肝脏胰岛素抵抗。而在C.虽然线虫已经显示当mTORC2信号传导被破坏时寿命增加，但是在哺乳动物中破坏mTORC2的效果是未知的。本文提出的工作将使用遗传方法来确定mTORC2信号传导减少对寿命的影响，并且还将检查mTORC2信号传导对CR饮食的影响的贡献。使用过表达mTORC2的关键成分Rictor的小鼠，我们将研究增加mTORC2促进长寿和增加抵抗高脂饮食对葡萄糖稳态的负面影响的能力。我们将使用基于质谱的方法来了解mTORC2在体内发挥的作用，并确定mTORC2调节的途径以及表征新的mTORC2底物。最后，我们将表征正常老化过程中的mTORC2信号传导。 这些目标将显著增加我们对mTOR信号通路在促长寿干预期间如何发挥作用的理解，并可能提高我们治疗衰老疾病而无不良副作用的能力。我们还将确定增加mTORC2信号传导是否可以改善肥胖对葡萄糖稳态的负面影响，确定mTORC2信号传导是否可以用于治疗2型糖尿病。我们基于质谱的方法将帮助我们更多地了解调节mTORC 2通路的体内后果，并帮助我们了解该通路在衰老过程中如何变化。 公共卫生相关性：糖尿病相关疾病，包括癌症、神经退行性疾病、心血管疾病和II型糖尿病，是当今西方社会发病率和死亡率的主要原因。这项提案中的工作旨在了解促长寿干预措施调节寿命以及葡萄糖水平和胰岛素敏感性的机制。这项工作还试图确定参与衰老过程的新靶点和细胞通路。

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) signaling pathway is a highly conserved pathway that regulates growth and metabolism in response to the availability of nutrients. mTOR signaling is inhibited by rapamycin, an FDA-approved compound widely used during transplantation surgery as an immunosuppressant, as well as in clinical trials for the treatment of cancer. Treatment with rapamycin extends the lifespan of many model organisms, including mice, and is beneficial for the treatment of diseases of aging, including Alzheimer's disease, in mouse models. Treatment with rapamycin, and inhibition of mTOR complex 1 (mTORC1), is proposed to promote longevity by a mechanism similar to that of calorie restricted (CR) diet, in which caloric intake is reduced while maintaining adequate nutrition. However, we have found that rapamycin also inhibits mTOR complex 2 (mTORC2), disrupting glucose homeostasis and increasing hepatic insulin resistance. While studies in C. elegans have shown increased longevity when mTORC2 signaling is disrupted, the effect of disrupting mTORC2 in mammals is unknown. The work proposed herein will use a genetic approach to determine the effects of decreased mTORC2 signaling on lifespan, and furthermore will examine the contribution of mTORC2 signaling to the effects of a CR diet. Using mice engineered to overexpress Rictor, a key component of mTORC2, we will examine the ability of increased mTORC2 to promote longevity and increase resistance to the negative effects of a high-fat diet on glucose homeostasis. We will use a mass spectrometry based approach to understand the role played by mTORC2 in vivo, and identify pathways regulated by mTORC2 as well as characterize novel mTORC2 substrates. Finally, we will characterize mTORC2 signaling during normal aging. These aims will significantly increase our understanding of how the mTOR signaling pathway functions during pro-longevity interventions, and potentially increase our ability to treat diseases of aging without undesirable side effects. We will also determine if increased mTORC2 signaling can ameliorate the negative consequences of obesity on glucose homeostasis, determining if mTORC2 signaling might be of therapeutic use for the treatment of type 2 diabetes. Our mass spectrometry-based approach will help us to learn more about the in vivo consequences of modulating the mTORC2 pathway, and help us learn about how this pathway changes during the aging process. PUBLIC HEALTH RELEVANCE: Age-related diseases, including cancer, neurodegenerative disorders, cardiovascular disease, and type II diabetes, are the major contributors to morbidity and mortality in Western society today. The work in this proposal aims to understand the mechanism by which pro- longevity interventions regulate lifespan as well as glucose levels and insulin sensitivity. This work also seeks to identify novel targets and cellular pathways involved in the aging process.