Small Proteins and Renal Urea Transport Regulation

小蛋白质和肾尿素转运调节

• 批准号: 8426166
• 负责人: Guangping Chen
• 金额: $ 32.53万
• 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/8426166
• 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.

性状（由申请人提供）：尿素在尿浓缩机制中起关键作用，因此在调节水平衡中起关键作用。虽然1993年第一个UT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辅助蛋白，可能在UT-A1成熟，运输，回收和降解中发挥关键的调节作用。本申请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。我们特别感兴趣的是一组小分子量蛋白质，如小窝蛋白-1和14-3-3蛋白。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。我们选择这三种候选蛋白，因为它们代表了三种在不同步骤以不同机制调节UT-A1的蛋白。了解这些相互作用是解剖UT-A1细胞内易位，膜运输以及回收/降解过程的关键步骤，这些过程都有助于在生理和病理条件下在肾脏中转运尿素。我们的研究不仅将为我们了解UT-A1细胞调控（运输，回收和降解）提供新的见解，还将为整个转运蛋白研究领域提供新的见解。 与Haian Fu博士和Emory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的小分子调节剂（前14- 3-3），这些蛋白质可以影响UT-A1在体内的功能，用于治疗高血压，充血性心力衰竭，肝硬化和肾病综合征等全身体液超负荷疾病的潜在治疗干预。