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：
8735013
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/8735013
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）：本研究计划的总体目标是利用生物化学、电生理学、代谢、遗传和整体研究，进一步阐明 mTORC2 靶点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意义。动物生理学技术。 K01导师职业发展奖的申请人Catherine E. Gleason博士目前是加州大学旧金山分校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交叉和影响控制各种生物功能的通路，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作为学术机构的终身教授研究员建立一个独立的分子生理学研究项目。 SGK1 和 Akt 是高度相关的蛋白激酶，分别作为控制离子和代谢稳态的信号通路的关键介质。最近，mTORC2 被确定为负责通过磷酸化这些激酶的疏水基序 (HM) 中的关键同源残基来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）会触发 SGK1 和 Akt 的磷酸化，因此 mTORC2 如何能够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代谢的不同影响不明白。值得注意的是，肾脏除了在离子平衡中发挥既定的作用外，还发挥着由于其显着的糖异生能力，在整个动物能量稳态中发挥着重要作用。目前尚不清楚肾脏如何能够对多个信号通路的串扰进行排序，以对其代谢和离子平衡功能进行适当的、依赖于环境的调节。因此，了解体外和体内 mTORC2 选择性激活 SGK1 和 Akt 的分子动力学是一个开放且重要的研究领域。 Gleason 博士将在代谢生理学和信号转导方面的背景基础上，接受离子转运过程的细胞和整体动物研究方面的额外培训，以解决 mTORC2 对 SGK1 与 Akt 的特异性的机制基础及其对细胞和整体的功能影响通过两个具体目标在动物水平上进行研究：1) 研究调节 SGK1 与 Akt 的 mTORC2 特异性激活的激素刺激和/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 Gleason 博士提供一个全面的工具箱，用于她研究新陈代谢与健康和疾病中多种信号通路的交叉点的独立职业生涯。