Small Proteins and Renal Urea Transport Regulation

小蛋白质和肾尿素转运调节

• 批准号: 8604389
• 负责人: Guangping Chen
• 金额: $ 33.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604389
• 关键词: 14-3-3 Proteins; Adrenergic Receptor; Affect; Binding; Binding Proteins; Biology; Body Fluids; Carrier Proteins; Caveolae; Caveolins; Cell Membrane Proteins; Cell Surface Proteins; Cell membrane; Cell physiology; Cell surface; Cells; Chemicals; Cholesterol; Cirrhosis; Collaborations; Complex; Congestive Heart Failure; Data; Disease; Duct (organ) structure; Epithelial Cells; Equilibrium; Family; Fluid overload; Goals; Hypertension; Intracellular Membranes; Intracellular translocation; Kidney; Knockout Mice; Ligands; Link; MDM2 gene; Mammals; Mediating; Membrane; Membrane Microdomains; Membrane Protein Traffic; Membrane Proteins; Molecular; Molecular Weight; Nephrotic Syndrome; Osmolar Concentration; Pathway interactions; Phosphorylation; Physiological; Play; Potassium Channel; Process; Protein Isoforms; Proteins; Rattus; Recruitment Activity; Recycling; Regulation; Research; Retrieval; Role; Scaffolding Protein; Sequence Analysis; Serine; Signal Transduction; Sodium; Sorting - Cell Movement; Specificity; Stimulus; Structural Protein; Therapeutic Intervention; Threonine; Time; Ubiquitination; Urea; Vasopressins; Water; Yeasts; caveolin 1; cell growth regulation; drug discovery; in vivo; insight; interest; protein function; protein phosphatase inhibitor-2; protein protein interaction; public health relevance; receptor internalization; response; salt sensitive; small molecule; solute; trafficking; urea transporter; urinary; yeast two hybrid system

DESCRIPTION (provided by applicant): Urea plays a critical role in the urinary concentrating mechanism and therefore in the regulation of water balance. Although the first UT was cloned in 1993 and significant progress was achieved, the molecular mechanisms for UT-A1 regulation in cells are still unclear. We recently identified a number of accessory proteins which might play critical regulatory roles in UT-A1 maturation, trafficking, recycling and degradation. The overall goal of the current application is to investigate how the protein- protein interaction regulates UT-A1 activity in cells. We are particularly interested in a group of small molecular weight proteins, such as caveolin-1 and 14-3-3 proteins. Our preliminary data show that these proteins can physically interact with UT-A1. We choose these three candidates since they represent three kinds of proteins that regulate UT-A1 at different steps with different mechanisms. Understanding these interactions is a critical step in dissecting the processes of UT-A1 intracellular translocation, membrane trafficking, as well as retrieval/degradation that all contribute to the urea transport in kidney under physiological and pathological conditions. Our study will not only provide us new insights to understand UT-A1 cellular regulation (trafficking, recycling and degradation) but also provide new insights in the entire transporter research field. In collaboration with Dr. Haian Fu and the Emory Chemical Biology Drug Discovery Center, our long-term project aim is to screen and develop small-molecule modulators of these proteins (first 14- 3-3) that could affect UT-A1 function in vivo for potential therapeutic interventions for the diseases with total body fluid overload such as hypertension, congestive heart failure, cirrhosis, and nephrotic syndrome.

描述（由申请人提供）：尿素在尿液浓缩机制中发挥着关键作用，因此在水平衡的调节中发挥着关键作用。尽管第一个UT于1993年被克隆并取得了重大进展，但UT-A1在细胞中调控的分子机制仍不清楚。我们最近发现了一些可能在 UT-A1 成熟、运输、回收和降解中发挥关键调节作用的辅助蛋白。当前应用的总体目标是研究蛋白质-蛋白质相互作用如何调节细胞中的 UT-A1 活性。我们对一组小分子量蛋白质特别感兴趣，例如 Caveolin-1 和 14-3-3 蛋白质。我们的初步数据表明这些蛋白质可以与 UT-A1 发生物理相互作用。我们选择这三个候选者，因为它们代表了三种以不同机制在不同步骤调节 UT-A1 的蛋白质。了解这些相互作用是剖析 UT-A1 细胞内易位、膜运输以及回收/降解过程的关键一步，这些过程都有助于生理和病理条件下肾脏中尿素的转运。我们的研究不仅将为我们提供了解 UT-A1 细胞调节（运输、回收和降解）的新见解，而且还将为整个转运蛋白研究领域提供新见解。 我们与付海安博士和埃默里化学生物学药物发现中心合作，我们的长期项目目标是筛选和开发这些蛋白质（前14-3-3）的小分子调节剂，这些调节剂可以影响体内UT-A1的功能，为高血压、充血性心力衰竭、肝硬化和肾病综合征等体液超负荷疾病提供潜在的治疗干预措施。