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

胰岛素在控制肾脏钠(Na+)重吸收中的作用具有特殊的临床意义。 重要性，因为它与代谢相关的高血压(胰岛素抵抗)有关 综合症。高胰岛素血症会导致不适当的肾脏钠离子处理，导致高血压。一个 胰岛素的主要作用部位是在醛固酮敏感的上皮性钠离子通道(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 聚集在主细胞的顶膜上。SGK1似乎有一种新的脂质相互作用 可能参与胰岛素激活SGK1的基序(PXL结构域)。这项提案的总体目标是 阐明胰岛素-PI3K信号通路激活SGK1的机制。这个 目标如下：(1)确定哪些磷脂酰肌醇对SGKI的能力是重要的 刺激ENaC转运；(2)评估SGK1激活是否需要PXL结构域；(3) 确定PXL结构域是否通过膜靶向调节SGK1的激活。这个 对这些途径的阐明可能会确定治疗这种形式的高血压的新途径， 随着我国肥胖率的上升，这种情况无疑会变得更加普遍。 除了建议的实验外，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，以帮助 作为一名肾病内科科学家，他是实现学术生涯长期目标的候选人。Dr。 大卫·皮尔斯是离子运输荷尔蒙调节领域的领导者，他将指导候选人的 科学发展观。此外，斯蒂芬·格鲁克博士是一位备受尊敬的离子细胞生理学专家 传输者和基思·莫斯托夫博士以及国际公认的上皮细胞贩运专家将 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召开会议，为科学和事业提供 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 为这位候选人做好准备，成为一名成功的内科科学家。

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.