REGULATION OF THE SODIUM CHLORIDE COTRANSPORTER

氯化钠协同转运蛋白的调节

• 批准号: 6903317
• 负责人: Robert S Hoover
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903317
• 关键词: Xenopus; Xenopus oocyte; clinical research; homeostasis; hormone regulation /control mechanism; ion transport; membrane transport proteins; phosphorylation; protein kinase C; protein structure function; receptor expression; serine threonine protein kinase; sodium chloride

DESCRIPTION (provided by applicant): My ultimate goal is to become a fully independent principal investigator with a basic science laboratory examining the molecular physiology of renal ion transport. After completing 6 years of training with Dr. Steven Herbert at 3 different institutions, I became an Assistant Professor at the University of Chicago. I have studied the regulation of the rat thiazide-sensitive sodium chloride cotransporter (rNCC) by glycosylation and phosphorylation for that period of time. I have demonstrated that rNCC is capable of being PKC phosphorylated in vitro, rNCC is functionally inhibited by PKC and there is a significant increase in baseline function and surface expression of rNCC with mutation of consensus PKC phosphorylation sites. With the support of this Career Development Award, the University of Chicago Department of Medicine, and my mentors, Dr. Herbert and Dr. Chang, I hope to continue to progress towards my long term goal. NCC is the site of action of one of the most commonly prescribed anti-hypertensive medications and plays a key role in divalent cation handling, yet we know little about it's regulation. This proposal will test the hypothesis that PKC and WNK4 kinase play a key role in regulation of NCC, predominantly by phosphorylation of serine and threonine residues resulting in decreased surface expression. The first specific aim will seek to define the role and mechanisms of WNK4 kinase, PKC and PKA in regulating the activity and surface expression of NCC. The second specific aim will seek to explore the physiological and hormonal regulation of the cotransporter and kinases, the physiological role of the cotransporter in divalent ion handling and the mechanisms underlying these processes. This investigation of the regulation of this effector of blood pressure and calcium homeostasis will provide invaluable insight into the pathogenesis of dysregulation of these homeostatic mechanisms.

描述(由申请人提供)：我的最终目标是成为一名完全独立的首席研究员，拥有一个研究肾脏离子转运的分子生理学的基础科学实验室。在与史蒂文·赫伯特博士一起在3所不同的机构接受了6年的培训后，我成为了芝加哥大学的助理教授。在这段时间里，我研究了糖基化和磷酸化对大鼠硫氮敏感的氯化钠协同转运体(RNCC)的调节作用。我已经证明，RNCC在体外能够被PKC磷酸化，RNCC被PKC功能抑制，随着共有的PKC磷酸化位点的突变，RNCC的基础功能和表面表达显著增加。在此次职业发展奖、芝加哥大学医学部以及我的导师赫伯特博士和张博士的支持下，我希望继续朝着我的长期目标前进。NCC是最常用的抗高血压药物之一的作用部位，在二价阳离子处理中发挥关键作用，但我们对其调节知之甚少。这一提议将检验一种假说，即PKC和WNK4激酶在NCC的调节中起关键作用，主要是通过丝氨酸和苏氨酸残基的磷酸化导致表面表达减少。第一个具体目标是确定WNK4激酶、PKC和PKA在调节NCC活性和表面表达中的作用和机制。第二个具体目标将寻求探索共转运蛋白和激酶的生理和激素调节，共转运蛋白在二价离子处理中的生理作用以及这些过程的潜在机制。这一血压和钙稳态效应因子的调节研究将为这些稳态机制失调的发病机制提供宝贵的洞察力。