Specifying Control Over Ion Balance and Glucose Homeostasis Through mTORC2

通过 mTORC2 指定对离子平衡和葡萄糖稳态的控制

基本信息

批准号：
8635679
负责人：
Catherine Gleason
金额：
$ 14.78万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2013-09-16 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635679
关键词：
Address Angiotensin II Animals Area Biochemical Biological Process Blood Pressure Cells Complex Cues Development Disease Electrolyte Balance Electrolytes Endocrinology Energy Metabolism Epithelial Equilibrium Genetic Gluconeogenesis Glucose Goals Growth Factor Health Homeostasis Hormonal Hormones Hypertension IGF1 gene In Vitro Institution Insulin Investigation Ion Transport Ions K-Series Research Career Programs KRP protein Kidney Knock-out Knockout Mice Laboratories Maintenance Mass Spectrum Analysis Mediating Mediator of activation protein Mentors Metabolic Metabolic Control Metabolic Diseases Metabolism Molecular Mus Nephrons Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Pathway interactions Phosphorylation Phosphotransferases Physiological Physiology Play Positioning Attribute Postdoctoral Fellow Process Protein Isoforms Proto-Oncogene Proteins c-akt Proximal Kidney Tubules Pyruvate Regulation Relative (related person)Research Research Personnel Research Proposals Role Sgk protein Signal Pathway Signal Transduction Site Sorting - Cell Movement Specific qualifier value Specificity Stimulus Substrate Specificity Techniques Training Transport Process Tubular formation base blood glucose regulation carbohydrate metabolism career deprivation energy balance epithelial Na+ channel glucose metabolism glucose production human FRAP1 protein in vivo insulin tolerance mTOR protein metabolic abnormality assessment molecular dynamics novel programs protein complex protein protein interaction public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to further elucidate the molecular mechanisms that underlie mTORC2 target specificity and their functional implications in the regulation of glucose homeostasis and ion balance, using biochemical, electrophysiological, metabolic, genetic and whole animal physiology techniques. The applicant for the K01 Mentored Career Development Award, Dr. Catherine E. Gleason, is currently a postdoctoral fellow in Dr. David Pearce's laboratory at UCSF. Dr. Gleason's long-term research goal is to study how metabolic signaling pathways intersect and influence pathways controlling various biological functions, notably ion balance by the kidney, for maintenance of physiological homeostasis. Dr. Gleason's long-term career goal is to establish an independent molecular physiology research program as a tenure-track investigator at an academic institution. SGK1 and Akt are highly related protein kinases that function as key mediators of the signaling pathways that control ion and metabolic homeostasis, respectively. Recently, mTORC2 was identified as the kinase responsible for activation of these kinases by phosphorylation of a critical, homologous residue in their hydrophobic motif (HM). Since, stimuli that induce mTORC2 activity, such as insulin and IGF1, trigger phosphorylation of both SGK1 and Akt, how mTORC2 is able to modulate activity of these related kinases in such a way that allows them to mediate distinct effects on electrolyte balance and energy metabolism is not understood. Notably, in addition to its well-established role in ion balance, the kidney also plays an important role in whole animal energy homeostasis due to its significant gluconeogenic capacity. It is unclear how the kidney is able to sort crosstalk from multiple signaling pathways to allow for appropriate, context-dependent regulation of its metabolic and ion balance functions. Thus, understanding the molecular dynamics surrounding mTORC2 selective activation of SGK1 and Akt, in vitro and in vivo, are open and important areas for investigation. Dr. Gleason will build on her background in metabolic physiology and signal transduction with additional training in the cellular and whole animal study of ion transport processes to address the mechanistic basis for mTORC2 specificity towards SGK1 vs. Akt and their functional implications at the cellular and whole animal levels through two specific aims: 1) Investigate the hormonal stimuli and/or cellular conditions that regulate mTORC2 specific activation of SGK1 vs. Akt. 2) Characterize the relative contributions of Akt and SGK1 towards renal glucose metabolism and ion balance in vivo. The training period provided by the K01 Mentored Career Development Award will provide Dr. Gleason with a comprehensive toolbox for her independent career investigating the intersections of metabolism with diverse signaling pathways in health and disease.

描述（由申请人提供）：这项研究建议的总体目标是进一步阐明MTORC2靶向特异性的分子机制及其在调节葡萄糖稳态和离子平衡中的功能含义，并使用生物化学，电生理学，代谢，整个，遗传和整个，遗传和整个，遗传，遗传和整个，遗传，遗传，遗传和整个动物生理技术。 K01指导职业发展奖的申请人Catherine E. Gleason博士目前是UCSF David Pearce博士实验室的博士后研究员。格里森博士的长期研究目标是研究代谢信号通路如何相交和影响控制各种生物学功能的途径，特别是肾脏的离子平衡，以维持生理稳态。格里森博士的长期职业目标是建立一个独立的分子生理研究计划，成为学术机构的终身调查员。 SGK1和AKT是高度相关的蛋白激酶，可作为控制离子和代谢稳态的信号传导途径的关键介体。最近，通过在其疏水基序中的关键，同源残基的磷酸化（HM），MTORC2被鉴定为负责激活这些激酶的激酶。由于诱导MTORC2活性的刺激（例如胰岛素和IGF1）触发SGK1和AKT的磷酸化，MTORC2如何能够以这种方式调节这些相关激酶的活性，从而使它们能够介导对电解质平衡和能量平衡的不同影响不了解。值得注意的是，除了其在离子平衡中的良好作用外，肾脏还发挥了作用由于其明显的糖原能力，在整个动物能量稳态中的重要作用。目前尚不清楚肾脏如何从多个信号通路中对串扰进行分类，以允许对其代谢和离子平衡功能进行适当的，依赖上下文的调节。因此，了解MTORC2选择性激活SGK1和AKT，体外和体内的分子动力学是开放且重要的研究领域。格里森博士将在其代谢生理学和信号转导的背景下建立在离子传输过程中的细胞和整个动物研究中的其他训练，以解决MTORC2特异性对SGK1的机械基础，而SGK1与AKT及其在细胞中的功能含义及其功能含义动物水平通过两个特定的目的：1）研究调节MTORC2特异性SGK1与AKT的激素刺激和/或细胞条件。 2）表征AKT和SGK1对体内肾葡萄糖代谢和离子平衡的相对贡献。 K01指导职业发展奖提供的培训期将为格里森博士提供全面的工具箱，以调查新陈代谢与健康和疾病中各种信号通路的交集。