Application for Research Supplement (diversity) for Kathryn A. Carbajal

7.项目总结/摘要 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， 调节生长和新陈代谢以响应营养素的可用性。mTOR信号传导被抑制， 雷帕霉素是一种FDA批准的化合物，广泛用于移植手术， 免疫抑制剂以及治疗癌症的临床试验。雷帕霉素治疗延长 延长许多模式生物体，包括小鼠的寿命，并且有益于治疗衰老疾病， 包括阿尔茨海默氏症的实验。 提出用雷帕霉素处理并抑制mTOR复合物1（mTORC 1）， 通过类似于热量限制（CR）饮食的机制延长寿命，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， （mT 0 RC 2），破坏葡萄糖稳态并增加肝胰岛素抵抗。而在C. 当mTORC 2信号传导被破坏时，线虫显示出寿命增加，破坏mTORC 2信号传导的效果是， 哺乳动物中的mTORC 2未知。本文提出的工作将使用遗传方法来确定 减少mTORC 2信号传导对寿命的影响，并将进一步研究mTORC 2的贡献。 这是一个信号的影响，CR饮食。使用过表达Rictor基因的小鼠， mTORC 2，我们将研究增加mTORC 2促进长寿和增加对 高脂肪饮食对葡萄糖稳态的负面影响。我们将使用基于质谱的 一种了解mTORC 2在体内所起作用的方法，并确定由mTORC 2调节的途径， 以及表征新型mTORC 2底物。最后，我们将在正常情况下表征mTORC 2信号传导。 衰老 这些目标将大大增加我们对mTOR信号通路功能的理解 在促进长寿的干预措施中，并有可能提高我们治疗衰老疾病的能力， 不良副作用。我们还将确定增加mTORC 2信号传导是否可以改善 肥胖对葡萄糖稳态的影响，确定mTORC 2信号传导是否可能是治疗性的 用于治疗2型糖尿病。我们基于质谱的方法将帮助我们了解更多 关于调节mTORC 2通路的体内后果，并帮助我们了解这是如何发生的。 在衰老过程中发生了变化。

7. Project Summary/Abstract 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.