Functional Role of the PXL Domain of SGK1 in Epithelial

SGK1 PXL 结构域在上皮细胞中的功能作用

• 批准号: 7023243
• 负责人: ALAN C PAO
• 金额: $ 12.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/7023243
• 关键词: Xenopus; Xenopus oocyte; enzyme activity; hormone regulation /control mechanism; hypertension; immediate early protein; insulin; ion transport; phosphatidylinositol 3 kinase; phosphatidylinositols; protein structure function; renal tubular transport; saluresis; serine threonine protein kinase; sodium channel; sodium ion

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）： 由于胰岛素与代谢（胰岛素抵抗）综合征相关的高血压相关，因此胰岛素在控制肾脏钠（Na+）重吸收中的作用具有特别的临床重要性。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在醛固酮敏感性远端肾单位中发现的上皮Na+通道（ENaC）上。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），SGK 1在刺激ENaC在主细胞顶膜积聚中起关键作用。SGK 1似乎有一个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。该提案的主要目的是阐明SGK 1如何被胰岛素-PI 3 K信号通路激活的机制基础。其目标如下：（1）确定哪些磷酸肌醇对SGK 1刺激ENaC转运的能力在功能上是重要的;（2）评估PXL结构域是否是SGK 1活化所需的;（3）确定PXL结构域是否通过膜靶向调节SGK 1活化。这些途径的阐明将可能为这种形式的高血压确定新的治疗途径，这无疑将随着我国肥胖流行病的不断上升而变得更加普遍。 除了拟议的实验，生物化学，细胞生物学和负责任的研究行为的教学课程将补充一个结构化的研究培训计划，以帮助候选人实现他的长期目标，作为一个医生，科学家在肾脏学的学术生涯。大卫博士皮尔斯，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，离子转运蛋白细胞生理学方面备受尊敬的专家Stephen Gluck博士和国际公认的上皮细胞贩运专家基思莫斯托夫博士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，提供科学和职业支持。UCSF提供科学专业知识和技术资源，为这位候选人作为一名医生科学家的成功职业生涯做好准备。