Regulation of Akt Signaling by Detergent Resistant Membrane Associated Protein ClipR-59

耐洗涤剂膜相关蛋白 ClipR-59 对 Akt 信号传导的调节

• 批准号: 9290610
• 负责人: KEYONG DU
• 金额: $ 39.38万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-14 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290610
• 关键词: Acyltransferase; Adipocytes; Adipose tissue; Affect; Blood Glucose; Complex; Cysteine; Detergents; Development; Diet; Energy Metabolism; Exhibits; Future; Goals; Human; Impairment; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Maintenance; Mammals; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Metabolic; Molecular; Mus; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peripheral; Phenotype; Phosphorylation; Phosphotransferases; Play; Prevention; Process; Protein Kinase; Proteins; Public Health; Regulation; Research; Resistance; Role; Scaffolding Protein; Signal Transduction; Specific qualifier value; Transgenic Mice; Transgenic Organisms; Tyrosine Phosphorylation; adipocyte differentiation; adipokines; adiponectin; base; blood glucose regulation; glucose metabolism; glucose tolerance; glucose transport; insulin mediators; insulin sensitizing drugs; insulin signaling; interest; knock-down; mouse model; new therapeutic target; novel; palmitoylation; pandemic disease; therapeutic target

Project Summary Ser/Thr protein kinase Akt is a central mediator of insulin metabolic action. Impairment in Akt activity results in type II diabetes, a globe pandemic that will remain major challenges to public health in foreseeable future. A primary mechanism under which Akt to participate in metabolic action is to promote glucose transport in adipose and muscle cells, a process that is requires Akt membrane compartmentalization. Our studies is to understand how Akt membrane compartmentalization is regulated. To such goal, we identified ClipR-59 as a regulator of Akt membrane compartmentalization and demonstrated that, by modulating Akt membrane compartmentalization, ClipR-59 regulates insulin dependent Glut4 membrane translocation and that ClipR-59 plays a role in the regulation of glucose and energy metabolism as transgenic expression of ClipR-59 in mouse adipose tissue lowered blood glucose level, increased glucose tolerance and led the mice against diet induced obesity. The current proposal is our continued effort to define the role of ClipR-59 in the regulation of whole body glucose homeostasis and the mechanism under which ClipR-59 regulates Akt signaling. Our hypothesis is that inactivation of ClipR-59 will lead to dysregulation of body glucose and energy metabolism, and Elmo2 and DHHC17, via their regulations of the interaction of Akt with ClipR-59 and ClipR-59 association with detergent resistant membrane, are the new regulators of Akt membrane compartmentalization. Specifically, we will determine a) how inducible inactivation of ClipR-59 in adipose tissue affects glucose homeostasis and the development of obesity; b) how scaffold protein Elmo2, through its insulin regulated interaction with ClipR-59, regulates Akt membrane compartmentalization and insulin dependent Glut4 membrane translocation and c) how cysteine palmitoyl acyltransferase DHHC17, through modulating ClipR-59 palmitoylation and detergent resistant membrane (DRM) association, regulates Akt membrane compartmentalization. Overall, our application will allow us further define the role of ClipR-59 in the regulation of Akt signaling and whole body glucose homeostasis and the molecular mechanism under which ClipR-59 regulates these processes. We believe successful conducting our proposal will undoubtedly advance our understanding of the regulation of insulin signaling and the development of type II diabetes.

项目概要 Ser/Thr 蛋白激酶 Akt 是胰岛素代谢作用的中心介质。 Akt 活性受损会导致 II 型糖尿病是一种全球流行病，在可预见的未来仍将是公共卫生的重大挑战。一个 Akt 参与代谢作用的主要机制是促进葡萄糖转运 脂肪和肌肉细胞，这个过程需要 Akt 膜区室化。我们的研究是为了 了解 Akt 膜区室化是如何调节的。为了实现这一目标，我们将 ClipR-59 确定为 Akt 膜区室化的调节器，并证明通过调节 Akt 膜 ClipR-59 调节胰岛素依赖性 Glut4 膜易位，并且 ClipR-59 ClipR-59 在小鼠中的转基因表达在葡萄糖和能量代谢的调节中发挥作用 脂肪组织降低了血糖水平，增加了葡萄糖耐量，并导致小鼠对抗饮食诱导的 肥胖。当前的提案是我们继续努力定义 ClipR-59 在整个监管中的作用 体内葡萄糖稳态以及 ClipR-59 调节 Akt 信号传导的机制。我们的假设 是ClipR-59失活会导致体内葡萄糖和能量代谢失调，而Elmo2 和 DHHC17，通过其对 Akt 与 ClipR-59 相互作用以及 ClipR-59 与 抗洗涤剂膜是 Akt 膜区室化的新调节因子。具体来说，我们 将确定 a) ClipR-59 在脂肪组织中的诱导失活如何影响葡萄糖稳态以及 肥胖的发展； b) 支架蛋白 Elmo2 如何通过其胰岛素调节与 ClipR-59 的相互作用， 调节 Akt 膜区室化和胰岛素依赖性 Glut4 膜易位，c) 半胱氨酸棕榈酰酰基转移酶 DHHC17 如何通过调节 ClipR-59 棕榈酰化和去污剂 抗性膜 (DRM) 关联，调节 Akt 膜区室化。总体而言，我们的 该应用将使我们能够进一步明确 ClipR-59 在 Akt 信号传导和全身调节中的作用 葡萄糖稳态以及 ClipR-59 调节这些过程的分子机制。我们 相信我们的建议的成功实施无疑将增进我们对监管的理解 胰岛素信号传导和 II 型糖尿病的发展。