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

7.项目摘要/摘要 哺乳动物雷帕霉素靶标(MTOR)信号通路是一条高度保守的通路 调节生长和新陈代谢，以回应营养的可用性。MTOR信令被抑制 雷帕霉素，一种FDA批准的化合物，在移植手术中广泛用作 免疫抑制剂，以及治疗癌症的临床试验。雷帕霉素延长治疗时间 包括小鼠在内的许多模式生物的寿命，并有利于治疗衰老疾病， 包括阿尔茨海默氏症，在小鼠模型中。 建议用雷帕霉素治疗和抑制mTOR复合体1(MTORC1)以促进 通过与卡路里限制(CR)饮食相似的机制延长寿命，在CR饮食中，卡路里摄入量减少，而 保持充足的营养。然而，我们发现雷帕霉素也抑制mTOR复合体2 (MTORC2)，扰乱血糖稳态，增加肝脏胰岛素抵抗。而在C. 当mTORC2信号被干扰时，优雅的人表现出更长的寿命，这是干扰的影响 哺乳动物中的mTORC2尚不清楚。这里提出的工作将使用遗传方法来确定 MTORC2信号减少对寿命的影响，并进一步研究mTORC2信号的贡献 暗示了CR饮食的效果。使用经过改造的小鼠过表达Rictor，Rictor是 MTORC2，我们将研究mTORC2增加的能力，以延长寿命和增加对 高脂饮食对血糖稳态的负面影响。我们将使用基于质谱学的 了解mTORC2在体内的作用，并确定mTORC2调控的途径为 以及表征新颖的mTORC2衬底。最后，我们将描述正常情况下mTORC2信号的特征 衰老。 这些目标将大大增加我们对mTOR信号通路如何发挥作用的理解 在促进长寿的干预中，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mTORC2信号是否可以改善负面影响 肥胖对血糖稳态的影响，确定mTORC2信号是否具有治疗作用 用于治疗2型糖尿病。我们基于质谱学的方法将帮助我们了解更多 关于调节mTORC2通路的体内后果，并帮助我们了解这是如何 衰老过程中途径的变化。

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.