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)： 胰岛素在控制肾脏钠(Na+)重吸收中的作用具有特别重要的临床意义，因为它与代谢(胰岛素抵抗)综合征相关的高血压有关。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。胰岛素的一个主要作用部位是在对醛固酮敏感的远端肾单位的上皮性Na+通道(ENaC)上。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)，SGK1在刺激ENaC在主细胞顶膜积聚中起关键作用。SGK1似乎有一个新的脂类相互作用基序(PXL结构域)，可能参与胰岛素激活SGK1。这个建议的主要目的是阐明SGK1如何被胰岛素-PI3K信号通路激活的机制基础。其目的如下：(1)确定哪些磷酸肌苷对SGK1的S刺激ENaC转运的能力具有重要作用；(2)评估PXL结构域是否是SGK1激活所必需的；(3)确定PXL结构域是否通过膜靶向调节SGK1的激活。这些途径的阐明可能会找到治疗这种形式的高血压的新途径，毫无疑问，随着我国肥胖症流行的增加，这种高血压将变得更加普遍。 除了建议的实验外，生物化学、细胞生物学和负责任的研究指导课程将补充结构化的研究培训计划，以帮助候选人实现其作为肾病内科科学家的学术生涯的长期目标。大卫·皮尔斯博士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。此外，离子转运体细胞生理学方面备受尊敬的斯蒂芬·格鲁克博士和国际公认的上皮细胞运输专家基思·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。职业发展咨询委员会还将定期召开会议，提供科学和职业支助。加州大学旧金山分校提供科学专业知识和技术资源，为这位候选人提供一个理想的环境，为他作为一名内科科学家的成功职业生涯做准备。