The Functional Role of the PXL Domain of SGK1 in Epithelial Sodium Transport

SGK1 PXL 结构域在上皮钠转运中的功能作用

• 批准号: 7599686
• 负责人: ALAN C PAO
• 金额: $ 11.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599686
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Advisory Committees; Aldosterone; Apical; Binding; Biochemistry; Biological Assay; Blood Pressure; Cell membrane; Cell physiology; Cells; Cellular biology; Clinical; Complement; Computer Simulation; Confocal Microscopy; Country; Cultured Cells; Data; Defect; Development; Distal; Environment; Epidemic; Epithelial; Epithelial Cells; Exposure to; Extracellular Fluid; Goals; Hyperinsulinism; Hypertension; In Vitro; Insulin; Insulin Resistance; Ion Transport; Ions; Kidney; Laboratories; Lead; Life; Lipids; Location; Maintenance; Mediating; Mediator of activation protein; Membrane; Mentors; Metabolic; Molecular; Mus; N-terminal; Nephrology; Nephrons; Obesity; Oocytes; Pathway interactions; Pattern; Phosphatidylinositols; Phospholipids; Phosphorylation; Phosphotransferases; Physicians; Play; Regulation; Research Personnel; Research Training; Resources; Role; Scientist; Sgk protein; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Sodium; Staining method; Stains; Structure; Surface; Syndrome; System; Technical Expertise; Testing; Threonine; Training Programs; Transcriptional Regulation; Xenopus laevis; apical membrane; base; career; design; epithelial Na+ channel; hormone regulation; in vivo; mutant; novel; programs; protein aminoacid sequence; research study; response; responsible research conduct; trafficking

The role of insulin in controlling sodium (Na+) reabsorption in the kidney is of particular clinical importance due to its relevance to hypertension associated with the metabolic (insulin resistance) syndrome. Hyperinsulinemia can lead to inappropriate renal Na+ handling, resulting in hypertension. A major site of insulin's action is on the epithelial Na+ channel (ENaC) found in the aldosterone-sensitive distal nephron. Insulin, through the phosphatidylinositide 3'-kinase (PI3K) signaling pathway, activates serum and glucocorticoid regulated kinase 1 (SGK1), which plays a key role in stimulating ENaC accumulation at the apical membrane of the principal cell. SGK1 appears to have a novel lipid interaction motif (PXL domain) that may participate in SGK1 activation by insulin. The broad objective of this proposal is to elucidate the mechanistic basis of how SGK1 is activated by the insulin-PI3K signaling pathway. The aims are the following: (1) Identify which phosphoinositides are functionally important for SGKI's ability to stimulate ENaC transport; (2) Evaluate whether the PXL domain is required for SGK1 activation; (3) Determine whether the PXL domain regulates SGK1 activation through membrane targeting. The elucidation of these pathways will likely identify novel avenues of treatment for this form of hypertension, which will undoubtedly become more prevalent with the rising obesity epidemic in our country. In addition to the proposed experiments, didactic coursework in biochemistry, cell biology, and the responsible conduct of research will complement a structured research training program to assist the candidate in achieving his long term goal for an academic career as a physician-scientist in nephrology. Dr. David Pearce, who is a leader in the field of hormone regulation of ion transport, will mentor the candidate's scientific development. Moreover, Dr. Stephen Gluck, a highly respected expert in cellular physiology of ion transporters, and Dr. Keith Mostov, and internationally recognized expert in epithelial cell trafficking, will provide scientific expertise in the design of experiments and interpretation of results. A professional development advisory committee will also convene at regular intervals to provide scientific and career support. UCSF offers the scientific expertise and the technical resources to provide an ideal environment for preparing this candidate for a successful career as a physician-scientist.

胰岛素在肾脏中控制钠（Na+）重吸收中的作用特别是临床 重要性由于与代谢相关的高血压相关（胰岛素抵抗）而引起的重要性 综合征。高胰岛素血症会导致不适当的肾脏Na+处理，从而导致高血压。一个 胰岛素作用的主要部位位于醛固酮敏感的上皮Na+通道（ENAC）上 远端肾单位。胰岛素通过磷脂酰肌醇3'-激酶（PI3K）信号通路，激活 血清和糖皮质激素调节的激酶1（SGK1），在刺激ENAC中起关键作用 在主要细胞的顶膜上积聚。 SGK1似乎具有新型的脂质相互作用 可能参与胰岛素激活SGK1激活的基序（PXL结构域）。该提议的广泛目标 是为了阐明如何通过胰岛素-PI3K信号通路激活SGK1的机械基础。这 目的如下：（1）确定哪些磷酸肌醇对SGKI的能力在功能上很重要 刺激ENAC运输； （2）评估是否需要SGK1激活的PXL结构域； （3） 确定PXL结构域是否通过膜靶向调节SGK1激活。这 阐明这些途径可能会确定这种高血压形式的新型治疗途径， 毫无疑问，随着我国肥胖流行的上升，这将变得更加普遍。 除了提出的实验外，生物化学，细胞生物学和 负责任的研究将补充一个结构化的研究培训计划，以协助 候选人在肾脏科医师科学家的学术生涯中实现了他的长期目标。博士 大卫·皮尔斯（David Pearce）是离子运输激素监管领域的领导者，将指导候选人的 科学发展。此外，史蒂芬·格鲁克（Stephen Gluck）博士是离子细胞生理学高度尊敬的专家 运输公司和基思·莫斯特夫（Keith Mostov）博士，以及上皮细胞贩运方面的国际认可的专家 在实验设计和结果解释方面提供科学专业知识。专业人士 发展咨询委员会还将定期开会以提供科学和职业 支持。 UCSF提供科学专业知识和技术资源，以提供理想的环境 为这位候选人做准备，以成功地担任医师科学家。