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：
7166073
负责人：
ALAN C PAO
金额：
$ 9.07万
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：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2007-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7166073
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

DESCRIPTION (provided by applicant): 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 SGK1'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.

描述（由申请人提供）：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重要性，因为它与代谢（胰岛素抵抗）综合征相关的高血压相关。高胰岛素血症可导致肾脏Na+处理不当，从而导致高血压。胰岛素作用的主要部位是醛固酮敏感的远端肾单位中的上皮 Na+ 通道 (ENaC)。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)，后者在刺激主细胞顶膜 ENaC 积累中发挥关键作用。 SGK1 似乎具有一种新的脂质相互作用基序（PXL 结构域），可能参与胰岛素对 SGK1 的激活。该提案的主要目标是阐明胰岛素-PI3K 信号通路如何激活 SGK1 的机制基础。目标如下： (1) 确定哪些磷酸肌醇对于 SGK1 刺激 ENaC 转运的能力具有重要功能； (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。对这些途径的阐明可能会为这种形式的高血压找到新的治疗途径，随着我国肥胖流行率的上升，这种形式的高血压无疑将变得更加普遍。除了拟议的实验之外，生物化学、细胞生物学和负责任的研究行为方面的教学课程将补充结构化的研究培训计划，以帮助候选人实现作为肾病学医师科学家的学术职业的长期目标。 David Pearce 博士是离子运输激素调节领域的领军人物，他将指导候选人的科学发展。此外，备受尊敬的离子转运蛋白细胞生理学专家 Stephen Gluck 博士和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。专业发展咨询委员会还将定期召开会议，提供科学和职业支持。加州大学旧金山分校提供科学专业知识和技术资源，为这位候选人作为一名成功的医师科学家提供一个理想的环境。