FUNCTION OF P-GLYCOPROTEIN IN KIDNEY CELLS

描述（改编自研究者摘要）： 耐药P-糖蛋白（PGP），人MDR 1和 鼠mdr 1或mdr 3基因是一种膜蛋白 化疗药物 它还可以运输疏水肽， 类固醇和许多亲脂性底物。 它以正常的 器官，包括肾脏，在那里它被认为是介导排泄的 异生物质 这项研究的目的是达到一个全球性的 了解PGP在肾脏中的功能。 这一目标将 通过一系列旨在探索 PGP在处理外源性底物和两种潜在的内源性 印刷受体. 以下假设有待检验：1）肾脏 在外源性物质的排泄中起着重要作用， PGP介导的转运的竞争者调节内源性 印刷受体. 2)外源性底物（阻滞剂）的存在 抑制潜在内源性底物的跨上皮转运。 3)功能性PGP表达于近曲小管顶端区 细胞 4)表明PGP表达于细胞顶膜，分泌疏水性 外源性物质和疏水内源性底物。 5)异生物质 抑制PGP介导的转运或其他底物，可能引起细胞 损害 6)前列腺素E2（PGE 2）是前列腺素E的内源性底物， 系膜细胞 7)活性维生素D3是一种内源性底物， 近曲小管细胞 实验从整个动物的研究延伸， 对肾小管功能的影响， 细胞运输，最后，直接评估运输 机制在一个简单的实验系统，即酵母膜囊泡 表达PGP。 这些方法包括清除，显微穿刺， 定量荧光、放射性示踪和分子生物学 技术. 这些实验的结果将提供新的信息 需要了解PGP在肾脏中的作用， 内源性（PGE 2和活性维生素D3）和外源性底物，以及它们的 肾小球系膜和近端小管细胞的相互作用。

DESCRIPTION (Adapted from Investigator's Abstract): The multidrug resistance P-Glycoprotein (PGP), the product of the human MDR1 and the murine mdr1 or the mdr3 genes is a membrane protein that extrudes chemotherapeutic drugs. It can also transport hydrophobic peptides, steroids and a number of lipophilic substrates. It is expressed in normal organs, including the kidney, where it is thought to mediate excretion of xenobiotics. The purpose of this research is to reach a global understanding of the function of PGP in the kidney. This goal will be achieved through out a series of experiments designed to explore the role of PGP in the handling of exogenous substrates and of two potential endogenous substrates. The following hypotheses are to be tested: 1) That the kidney plays an important role in the excretion of xenobiotics, and that xenobiotic competitors for PGP-mediated transport modulate extrusion of endogenous substrates. 2) That the presence of exogenous substrates (blockers) inhibits the transepithelial transport of potential endogenous substrates. 3) That functional PGP is expressed in the apical domain of proximal tubule cells. 4) That PGP expressed in the apical membrane excrete hydrophobic xenobiotics and hydrophobic endogenous substrates. 5) That xenobiotics inhibit PGP-mediated transport or other substrates, potentially causing cell damage. 6) That prostaglandin E2 (PGE2) is a PGP endogenous substrate in mesangial cells. 7) That active Vitamin D3 is an endogenous substrate in proximal tubule cells. Experiments extend from studies in the whole animal, to the function of tubular segments, the study of transepithelial and cellular transport and, finally, to the direct assessment of transport mechanisms in a simple experimental system, namely yeast membrane vesicles expressing PGP. The methods include clearance, micropuncture, quantitative-fluorescence, radioactive-tracer and molecular-biology techniques. The results of these experiments will provide new information needed to understand the role of PGP in the kidney in the transport of endogenous (PGE2 and active Vitamin D3) and exogenous substrates, and their interactions in mesangial and proximal tubule cells.