FUNCTION OF P-GLYCOPROTEIN IN KIDNEY CELLS

P-糖蛋白在肾细胞中的功能

• 批准号: 2608460
• 负责人: ELSA N. BELLO-REUSS
• 金额: $ 24.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2608460
• 关键词: P glycoprotein; cholecalciferol; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; mesangium; micropuncture; multidrug resistance; prostaglandin E; protein structure function; renal tubular transport; tissue /cell culture

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.

描述（根据调查员的摘要改编）：多饮 抗性P-糖蛋白（PGP），人类MDR1和 鼠MDR1或MDR3基因是一种挤出的膜蛋白 化学治疗药物。 它也可以运输疏水肽， 类固醇和许多亲脂性底物。 它以正常状态表达 器官，包括肾脏，被认为可以介导 异种生物。 这项研究的目的是达到全球 了解PGP在肾脏中的功能。 这个目标将是 通过一系列旨在探索的作用，实现了 PGP在处理外源性基材和两个潜在内源性的pgp中 基材。 要测试以下假设：1）肾脏 在异种生物的排泄中起重要作用，而异生物生物 PGP介导的运输调节内源性挤出的竞争者 基材。 2）存在外源底物（阻滞剂） 抑制潜在的内源性底物的旋转转运。 3）功能性PGP在近端小管的顶端域表示 细胞。 4）在顶膜排泄疏水中表达的PGP 异种生物和疏水性内源性底物。 5）异生物学 抑制PGP介导的转运或其他底物，可能导致细胞 损害。 6）前列腺素E2（PGE2）是PGP内源性底物 肾小球细胞。 7）活性维生素D3是一种内源性底物 近端小管细胞。 实验从整个动物的研究中延伸 对于肾小管段的功能，跨索的研究和 细胞运输，最后直接评估运输 简单的实验系统中的机制，即酵母膜囊泡 表达PGP。 这些方法包括清除率，微函数， 定量荧光，放射性跟踪和分子生物学 技术。 这些实验的结果将提供新信息 需要了解PGP在肾脏中的作用 内源性（PGE2和活性维生素D3）和外源底物，它们 肾小管和近端小管细胞中的相互作用。