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

胰岛素在控制肾脏钠重吸收中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， 综合征高胰岛素血症可导致肾脏Na+处理不当，从而导致高血压。一 胰岛素作用的主要部位是在醛固酮敏感性细胞中发现的上皮Na+通道（ENaC）上。 远端肾单位胰岛素通过磷脂酰肌醇3 '-激酶（PI 3 K）信号通路激活 血清和糖皮质激素调节激酶1（SGK 1），其在刺激ENaC中起关键作用 在主细胞的顶膜处积累。SGK 1似乎具有新的脂质相互作用 基序（PXL结构域）可能参与胰岛素激活SGK 1。本提案的总体目标是 阐明SGK 1如何被胰岛素-PI 3 K信号通路激活的机制基础。的 目的如下：（1）确定哪些磷酸肌醇对于SGKI的能力在功能上是重要的， 刺激ENaC转运;（2）评估PXL结构域是否是SGK 1激活所需;（3） 确定PXL结构域是否通过膜靶向调节SGK 1活化。的 对这些途径的阐明将可能确定治疗这种形式的高血压的新途径， 随着肥胖症在我国的流行，这无疑将变得更加普遍。 除了建议的实验，生物化学，细胞生物学和生物化学的教学课程， 负责任的研究行为将补充结构化的研究培训计划，以帮助 候选人在实现他的长期目标的学术生涯作为一个医生，科学家在肾脏病。博士 大卫皮尔斯，谁是在离子运输激素调节领域的领导者，将指导候选人的 科学发展此外，斯蒂芬·格鲁克博士，一位备受尊敬的离子细胞生理学专家， 转运，和博士基思莫斯托夫，和国际公认的专家在上皮细胞贩运，将 在实验设计和结果解释方面提供科学专业知识。专业 发展咨询委员会也将定期召开会议， 支持.加州大学旧金山分校提供科学的专业知识和技术资源，以提供一个理想的环境， 为这位候选人成为一名成功的物理学家和科学家做好准备。

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.