The Functional Role of GilZ in Epithelial Sodium Transport

GilZ 在上皮钠转运中的功能作用

• 批准号: 7884247
• 负责人: Rama Soundararajan
• 金额: $ 12.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884247
• 关键词: Accounting; Address; Advisory Committees; Affect; Aldosterone; Apical; Binding; Biochemical; Biological Models; Biotinylation; Blood Pressure; Bypass; Cell Culture Techniques; Cell Fractionation; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Complement; Congestive Heart Failure; Data; Development; Disease; Distal; Dominant-Negative Mutation; Duct (organ) structure; Dynamin; Endocytosis; Epithelial; Epithelial Cells; Equilibrium; Event; Exocytosis; Extracellular Fluid; Extracellular Signal Regulated Kinases; GTP Binding; Generations; Genes; Glucocorticoids; Goals; Golgi Apparatus; Human; Hypertension; In Vitro; Ion Transport; Ions; Kidney; Lead; Leucine Zippers; Link; Literature; MEKKs; Maintenance; Malignant Hypertension; Mediating; Mediator of activation protein; Membrane; Membrane Protein Traffic; Mentors; Metabolic syndrome; Mineralocorticoid Receptor; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Molecular; Nephrons; Pathway interactions; Phosphotransferases; Physiological; Play; Probability; Process; Property; Proteins; Proto-Oncogene Proteins c-raf; RNA Interference; Recycling; Regulation; Renal function; Research; Resources; Role; Scientist; Signal Pathway; Signal Transduction; Sodium; Sodium Channel; Stroke; Structure; Techniques; Testing; Training; Training Programs; Transmembrane Transport; Work; Xenopus oocyte; apical membrane; base; career; collecting tubule structure; design; epithelial Na+ channel; hormone regulation; human MAP3K1 protein; inhibitor/antagonist; interest; kidney epithelial cell; mutant; novel; novel strategies; patch clamp; raf Kinases; receptor; research study; responsible research conduct; salt sensitive; trafficking

DESCRIPTION (provided by applicant): Understanding how the kidney functions to maintain normal sodium balance is particularly important because even subtle disruptions in this equilibrium play a role in most (if not all) cases of high blood pressure, that can lead to malignant hypertension, stroke or even death. The epithelial sodium channel, ENaC, is the physiologic mediator of sodium reabsorption by the kidney, and the rate-limiting step in this process as well. Recent work has shown the potential significance of a small aldosterone-regulated protein called GilZ, in profoundly stimulating the activity of ENaC, by markedly down-regulating the inhibitory ERK1/2 Mitogen Activated Protein Kinase pathway. The broad objective of this project is to systematically investigate how GilZ affects ENaC expression/function, using a combination of biochemical, immuno-cytochemical and electrophysiological approaches in in-vitro and cell culture model systems. Specifically, the proposed experiments aim to (1) characterize the mechanistic aspects of GilZ inhibition of ERK, (2) elucidate the mechanistic basis and physiological relevance of GilZ and ERK regulation of ENaC function, and (3) examine the molecular mechanisms of GilZ and ERK regulation of ENaC trafficking and open probability. The elucidation of these pathways will likely identify novel approaches for regulating this process in disease states such as congestive heart failure, metabolic syndrome and salt-sensitive hypertension. In addition to the proposed experiments, didactic coursework in signal transduction, membrane transport, and the responsible conduct of research will complement the structured training program to assist the candidate in achieving her long-term goal for an academic career as a successful research scientist in the field of ion transport and epithelial cell signaling. Dr. Pearce, a leader in the field of hormonal regulation of ion transport, will directly mentor the candidate's scientific development. In addition, Drs. Gluck, Mostov, and Humphreys, who are renowned experts in cellular physiology of ion transporters and membrane 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 appropriate scientific and career support. UCSF thus offers the technical resources, scientific expertise and structured mentoring required for training the candidate for a successful career in her chosen field.

描述（由申请人提供）： 了解肾脏如何保持正常的钠平衡功能特别重要，因为即使这种平衡的微妙破坏在大多数（如果不是全部）高血压病例中也起作用，这可能导致恶性高血压，中风甚至死亡。上皮钠通道ENAC是肾脏钠重吸收的生理介质，也是此过程中的限制步骤。最近的工作表明，通过明显下调抑制性ERK1/2有丝分裂激活的蛋白激酶途径的抑制性ERK1/2，一种称为GILZ的小型醛固酮调节的蛋白质的潜在意义。该项目的广泛目的是系统地研究吉尔兹在体外和细胞培养模型系统中的生化，免疫环化学和电生理方法的组合。具体而言，所提出的实验旨在（1）表征GILZ抑制ERK的机械方面，（2）阐明GILZ和ERK调节ENAC功能的机械基础和生理相关性，（3）检查GILZ和ERK调节ENAC运输和开放率和开放率和开放率的分子机制。这些途径的阐明可能会确定在疾病状态（如充血性心力衰竭，代谢综合征和盐敏感性高血压）中调节这一过程的新方法。 除了提出的实验外，信号转导，膜运输和负责任的研究的教学课程还将补充结构化培训计划，以帮助候选人实现她作为离子运输领域成功的研究科学家学术生涯的长期目标。 Pearce博士是离子运输荷尔蒙调节领域的领导者，将直接指导候选人的科学发展。另外，博士。 Gluck，Mostov和Humphreys是离子转运蛋白和膜贩运细胞生理学专家的著名专家，将在实验设计和结果解释方面提供科学专业知识。专业发展咨询委员会还将定期召集，以提供适当的科学和职业支持。因此，UCSF提供了培训候选人在她选择的领域成功职业所需的技术资源，科学专业知识和结构化指导。