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

基本信息

批准号：
7575925
负责人：
ALAN C PAO
金额：
$ 2.89万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/7575925
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 Condition 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 Rate Regulation Research 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 trafficking

项目摘要

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.

胰岛素在控制肾脏钠 (Na+) 重吸收方面的作用具有特殊的临床意义由于其与代谢（胰岛素抵抗）相关的高血压的相关性而具有重要性综合症。高胰岛素血症可导致肾脏Na+处理不当，从而导致高血压。一个胰岛素的主要作用位点是醛固酮敏感细胞中的上皮 Na+ 通道 (ENaC) 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激酶 1 (SGK1)，在刺激 ENaC 中发挥关键作用积聚在主细胞的顶膜上。 SGK1 似乎具有新颖的脂质相互作用可能参与胰岛素激活 SGK1 的基序（PXL 结构域）。该提案的总体目标目的是阐明胰岛素-PI3K信号通路如何激活SGK1的机制基础。这目标如下： (1) 确定哪些磷酸肌醇对于 SGKI 的能力具有重要功能刺激 ENaC 运输； (2)评估SGK1激活是否需要PXL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找到治疗这种高血压的新途径，随着我国肥胖流行率的上升，这种现象无疑会变得更加普遍。除了拟议的实验之外，还提供生物化学、细胞生物学和负责任的研究行为将补充结构化的研究培训计划，以协助候选人实现其作为肾脏病学医师科学家的学术生涯的长期目标。博士。 David Pearce 是离子运输激素调节领域的领军人物，他将指导候选人科学发展。此外，备受尊敬的离子细胞生理学专家Stephen Gluck博士国际公认的上皮细胞运输专家 Keith Mostov 博士将提供实验设计和结果解释方面的科学专业知识。专业人士发展咨询委员会也将定期召开会议，提供科学和职业指导支持。加州大学旧金山分校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作为一名成功的医师科学家做好准备。