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

凯瑟琳·A·卡巴哈尔 (Kathryn A. Carbajal) 的研究补助（多样性）申请

基本信息

批准号：
9015712
负责人：
Dudley William Lamming
金额：
$ 0.75万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9015712
关键词：
Adipose tissue Adult Adverse effects Affect Aging Aging-Related Process Alleles Alzheimer&apos s Disease Animal Model Animals Biological Assay Biology Brain Caenorhabditis elegans Caloric Restriction Cardiovascular Diseases Chronic Clinical Treatment Clinical Trials Complex Diabetes Mellitus Diet Disease Embryonic Development Energy Intake Engineering FDA approved Fasting Fatty acid glycerol esters Genetic Glucose Glucose Intolerance Growth Health Hepatic Immunosuppressive Agents Insulin Resistance Intervention Learning Liver Longevity Malignant Neoplasms Mammals Maps Mass Spectrum Analysis Mentors Metabolism Morbidity - disease rate Mus Muscle Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Transplantation Pathway interactions Phase Physiology Play Protein Kinase Proteins Regulation Research Resistance Role Signal Pathway Signal Transduction Sirolimus Societies Therapeutic Uses TimeLine Tissues Validation Work Yeasts abstracting age effect age related base blood glucose regulation cellular targeting dietary restriction feeding fly genetic approach glucose metabolism human FRAP1 protein impaired glucose tolerance improved in vivo insulin sensitivity mTOR protein member mortality mouse model normal aging novel nutrition overexpression response

项目摘要

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.

7。项目摘要/摘要雷帕霉素（MTOR）信号通路的哺乳动物靶标是一种高度保守的途径根据养分的可用性，调节生长和代谢。 MTOR信号传导被抑制雷帕霉素是一种FDA批准的化合物，在移植手术中广泛使用免疫抑制剂以及用于治疗癌症的临床试验。用雷帕霉素治疗延伸许多模型生物的寿命，包括小鼠，对治疗衰老疾病的治疗是有益的包括阿尔茨海默氏病，包括小鼠模型。提出用雷帕霉素和抑制MTOR复合物1（MTORC1）的治疗来促进通过类似于卡路里限制（CR）饮食的机制的寿命，在这种机制中，热量摄入量减少而又维持足够的营养。但是，我们发现雷帕霉素还抑制MTOR复合物2 （MTORC2），破坏葡萄糖稳态并增加肝胰岛素抵抗。而在C中进行研究当MTORC2信号被破坏时，秀丽隐杆线的寿命增加，破坏的效果哺乳动物中的MTORC2尚不清楚。本文提出的工作将使用遗传方法来确定 MTORC2信号降低对寿命的影响，此外将检查MTORC2的贡献信号向CR饮食的影响。使用工程过表达rictor的小鼠，这是 MTORC2，我们将研究增加MTORC2促进寿命和增加对的能力高脂饮食对葡萄糖稳态的负面影响。我们将使用基于质谱的了解MTORC2在体内扮演的作用的方法，并将MTORC2调节的途径确定为以及新型MTORC2底物的特征。最后，我们将在正常情况下表征MTORC2信号老化。这些目标将大大提高我们对MTOR信号通路如何功能的理解在促态度干预措施中，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MTORC2信号增加是否可以改善负肥胖对葡萄糖稳态的后果，确定MTORC2信号是否可能具有治疗性用于治疗2型糖尿病。我们的基于质谱的方法将帮助我们了解更多关于调节MTORC2途径的体内后果，并帮助我们了解如何途径在老化过程中发生变化。