FUNCTION OF P-GLYCOPROTEIN IN KIDNEY CELLS

描述(改编自《调查者摘要》)：多种药物 耐药P-糖蛋白(Pgp)，人多药耐药基因和 小鼠mdr1或mdr3基因是一种膜蛋白， 化疗药物。它还可以运输疏水性多肽， 类固醇和一些亲脂底物。它在正常情况下表达 肾，包括肾在内的器官，在那里它被认为能调节 外源生物。这项研究的目的是为了在全球范围内 对Pgp在肾脏中作用的认识。这个目标将是 通过一系列实验来实现，旨在探索 PGP在处理外源底物和两种潜在内源物质中的作用 底物。以下假设需要检验：1)肾脏 在外源生物的排泄中起着重要作用，而外源生物 PGP介导转运的竞争对手调节内源蛋白的排出 底物。2)外源底物(阻滞剂)的存在 抑制潜在内源性底物的跨上皮运输。 3)功能性Pgp在近端小管的顶端表达 细胞。4)Pgp表达于顶膜排泄疏水性 外源物质和疏水性内源底物。5)外源生物 抑制PGP介导的转运或其他底物，可能导致细胞 损坏。6)前列腺素E_2(PGE_2)是PGP的内源性底物 系膜细胞。7)活性维生素D3是体内的底物 近端小管细胞。实验从对整个动物的研究延伸而来， 对肾小管节段的功能，跨上皮细胞和 蜂窝运输，最后是对运输的直接评估 一个简单的实验系统，即酵母膜囊泡的作用机理 表达Pgp。方法包括清除，显微穿刺法， 定量荧光、放射性示踪和分子生物学 技巧。这些实验的结果将提供新的信息 需要了解PGP在肾脏转运中的作用 内源(PGE2和活性维生素D3)和外源底物及其 系膜细胞和近端肾小管细胞间的相互作用。

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.