Regulation of Apical Traffic in Renal Epithelial Cells

描述(由申请人提供)： 肾细胞的功能需要维持具有不同蛋白质和脂肪组成的极化的质膜结构域。这在一定程度上是通过将新合成和再循环的膜蛋白定向输送到根尖或基底外侧表面来实现的。顶端分选信号非常不同，包括依赖于肽、脂和糖的基序。有趣的是，来自我们和其他实验室的最新数据表明，具有不同靶向的顶端蛋白在不同的运输载体群体中运输到表面。这些高尔基体后载体可以直接运输到细胞表面；然而，最近的研究表明，一些新合成的蛋白质在到达细胞表面的途中运输回收内小体。我们的长期目标是确定引导新合成蛋白质顶端传递的信号，并了解这些信号在生物合成和内吞后途径的不同阶段是如何解释的。本研究的目的是确定在肾上皮细胞中调节到达心尖表面的不同途径的蛋白质，评估内细胞室在不同种类的心尖蛋白极化生物合成运输中的作用，并剖析沿生物合成和细胞后途径的糖依赖分选的机制。我们的研究结果将加深我们对生理相关分子上的运输线索如何在不同的细胞内位置进行解释以实现适当分选的理解。 项目叙事 肾脏的主要功能是将水、离子和代谢产物从形成的尿液重新吸收到血液中。肾脏细胞的表面被细分为面向尿液和血流的不同区域，这些区域包含不同的蛋白质和脂肪；这种表面成分的不对称分布对正常的肾脏功能至关重要。我们的目标是了解肾脏细胞如何创建和维持这些不同的表面域。我们的研究结果将提供关键的基本信息，可用于设计潜在的治疗方案来对抗与肾脏相关的疾病，包括肾癌、急性肾功能衰竭和高血压。

DESCRIPTION (provided by applicant): Renal cell function requires the maintenance of polarized plasma membrane domains with distinct protein and lipid compositions. This is accomplished in part by the targeted delivery of newly synthesized and recycling membrane proteins to the apical or basolateral surface. Apical sorting signals are extraordinarily diverse and include peptide-, lipid- and glycan-dependent motifs. Interestingly, recent data from our and other laboratories suggest that apical proteins with different targeting signals traffic to the surface in distinct populations of transport carriers. These post-Golgi carriers may traffic directly to the cell surface; however, recent studies suggest that some newly-synthesized proteins transit recycling endosomes en route to the cell surface. Our long term goals are to identify the signals that direct apical delivery of newly- synthesized proteins, and to understand how these signals are interpreted at various stages along the biosynthetic and postendocytic pathways. The aims of this proposal are to identify proteins that regulate distinct pathways to the apical surface in renal epithelial cells, to assess the role of endocytic compartments in the polarized biosynthetic traffic of different classes of apical proteins, and to dissect the mechanism of glycan-dependent sorting along the biosynthetic and postendocytic pathways. The results of our studies will refine our understanding of how transport cues on physiologically relevant molecules are interpreted at distinct intracellular sites to enable proper sorting. PROJECT NARRATIVE The primary function of the kidney is the reabsorption of water, ions, and metabolites from the forming urine to the bloodstream. The surfaces of kidney cells are subdivided into different domains that face the urine and bloodstream and which contain distinct proteins and lipids; and this asymmetric distribution of surface components is essential for proper kidney function. Our goal is to understand how kidney cells create and maintain these distinct surface domains. The results of our research will provide critical basic information that can be applied to the design of potential therapies to combat kidney-related diseases including renal carcinoma, acute renal failure, and hypertension.