Regulation of ENaC by phosphatidylinositide 3-kinase and phospholipids

磷脂酰肌醇 3-激酶和磷脂对 ENaC 的调节

• 批准号: 7572877
• 负责人: James D Stockand
• 金额: $ 28.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7572877
• 关键词: 1-Phosphatidylinositol 3-Kinase; 1-Phosphatidylinositol 4-Kinase; Address; Aldosterone; Amino Acids; Arts; Binding Sites; Blood Pressure; Colon; Coupling; Disease; Distal; Elements; Endocrine; Epithelium; Equilibrium; Experimental Designs; Figs - dietary; Functional disorder; Funding; Goals; Hormones; Human; Insulin; Investigation; Kidney; Lung; Mediating; Membrane; Methodology; Molecular; Nephrons; Phosphatidylinositols; Phospholipids; Phosphotransferases; Physiological; Play; Probability; Publishing; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Site; Sodium Chloride; Structure; System; Testing; Tissues; Vertebrates; Work; blood pressure regulation; epithelial Na+ channel; novel; phosphatidylinositol 3,4,5-triphosphate; phosphoinositide-3,4,5-triphosphate; renal epithelium; research study; response; second messenger; success

DESCRIPTION (provided by applicant): Regulated Na+ reabsorption at the distal nephron, in part, controls blood pressure in humans and other terrestrial vertebrates. Activity of the aldosterone-sensitive epithelial Na+ channel (ENaC) is limiting for Na+ transport here. Dysfunction and inappropriate regulation of ENaC result in blood pressure disorders and improper salt handling by the kidney, colon and lungs. This proposal is a competitive renewal of an R01 investigating aldosterone regulation of ENaC that has had much success during its initial funding period. Results from this initial funding period, as well as, newer preliminary results strongly suggest that phospholipid kinases, including phosphatidylinositide 3-kinase (PI3-K), and their product phosphatidylinositides are critical determinants of ENaC activity. Two physiologically important hormones that increase ENaC activity, aldosterone and insulin, increase P3-K activity and synthesis of its product phosphatidylinositol, phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), in distal nephron epithelia. The cellular mechanism underpinning this increase remains unknown. The extent to which PI3-K is the primary arbiter of aldosterone and insulin actions on ENaC, in addition, remains unexplored. Moreover, possible mechanisms and physiological consequences of PI(3,4,5)P3 modulation of ENaC are not fully appreciated. Putative molecular determinants within ENaC responsive to PI(3,4,5)P3 signaling, similarly, remain to be identified. The general hypothesis that PI3-K and its phosphatidylinositide products are central to regulation of ENaC unites the experiments and ideas of this proposal. This line of inquiry is a logical extension of my earlier studies, and I expect testing it to result in novel and significant findings. Here, I address three specific aims: 1) Delineate and assign physiological significance to PI3-K and PI(3,4,5)P3 signaling pathways targeting ENaC; 2) Determine the cellular mechanism of PI(3,4,5)P3 regulation of ENaC; and 3) Establish the molecular determinants within ENaC of PI(3,4,5)P3 regulation. I test my hypotheses with a comprehensive experimental design structured with complementary experiments to provide an integrative understanding of ENaC regulation by PI3-K from the molecule to the whole tissue. Proper Na+ reabsorption at the distal renal nephron in humans and other terrestrial vertebrates is central to regulation of systemic Na+ balance and thus, blood pressure. Activity of the aldosterone-sensitive epithelial Na+ channel (ENaC) is limiting for Na+ reabsorption here. The current proposal continues our investigation of the cellular and molecular mechanisms controlling ENaC activity in response to aldosterone.

描述（由申请人提供）： 调节远端的Na+重吸收部分，部分控制着人类和其他陆地脊椎动物的血压。醛固酮敏感的上皮Na+通道（ENAC）的活性限制了Na+运输的限制。功能障碍和不适当的ENAC调节导致血压障碍和肾脏，结肠和肺部处理不当。该提案是R01调查醛固酮调节ENAC的竞争性更新，该调查在其初始资金期间取得了很大的成功。最初的资助期以及较新的初步结果的结果强烈表明，包括磷脂酰肌醇3-激酶（PI3-K）在内的磷脂激酶及其产物磷脂酰固醇的产物是eNAC活性的关键决定因素。两种在生理上重要的激素，增加了ENAC活性，醛固酮和胰岛素，增加P3-K活性以及其产物磷脂酰肌醇的合成，磷脂酰肌醇3,4,5-三磷酸（PI（3,4,5）P3），在遥足上皮中。支撑此增加的细胞机制仍然未知。另外，PI3-K是醛固酮和胰岛素作用的主要仲裁体的程度，此外仍然没有探索。此外，PI（3,4,5）P3调节ENAC的可能机制和生理后果尚未完全理解。类似地，对Pi（3,4,5）P3信号反应的ENAC内的推定分子决定因素仍然有待鉴定。 PI3-K及其磷脂酰肌醇产物的总体假设对于ENAC的调节至关重要。这种探究线是我早期研究的逻辑扩展，我希望它测试它会导致新颖而重要的发现。在这里，我解决了三个具体目的：1）划定并为PI3-K和PI（3,4,5）P3信号传导途径划分生理意义； 2）确定PI（3,4,5）P3 ENAC的细胞机制； 3）在PI（3,4,5）P3调节的ENAC中建立分子决定因素。我通过通过互补实验结构的全面实验设计来检验我的假设，以对PI3-K从分子到整个组织的ENAC调节进行整合的了解。在人类和其他陆脊椎动物的远端肾脏肾单位上的适当Na+重吸收对于系统性Na+平衡的调节和血压是至关重要的。醛固酮敏感的上皮Na+通道（ENAC）的活性限制了Na+重吸收。当前的建议继续我们研究控制醛固酮的ENAC活性的细胞和分子机制。