Small Proteins and Renal Urea Transport Regulation

小蛋白质和肾尿素转运调节

基本信息

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
项目类别：
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

项目摘要

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起着至关重要的作用，因此在水平的调节中起着至关重要的作用。尽管第一个UT于1993年克隆并取得了重大进展，但仍不清楚细胞中UT-A1调节的分子机制。我们最近确定了许多附件蛋白，这些蛋白可能在UT-A1成熟，贩运，回收和降解中起关键的调节作用。当前应用的总体目标是研究蛋白质蛋白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（例如小窝1和14-3-3蛋白）特别感兴趣。我们的初步数据表明，这些蛋白质可以与UT-A1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蛋白质，这些蛋白质在不同机制的不同步骤下调节UT-A1。理解这些相互作用是剖析UT-A1细胞内易位，膜运输以及检索/降解的关键步骤，这些过程在生理和病理条件下都有助于肾脏的尿素运输。我们的研究不仅将为我们提供新的见解，以了解UT-A1细胞调节（运输，回收和退化），而且还提供了整个运输者研究领域的新见解。 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.