RENAL ORGANIC CATION--SPECIFICITY AND ENERGETICS

有机阳离子（和碱;统称为“OC”）包括多种多样的 生理学、药理学和毒理学的分子 本案无关肾脏中的转运过程，特别是 近端小管在调节这些化合物的水平中起主要作用 在体内我们寻求理解有机生物体 阳离子进入、离开并积累在肾细胞内。在 特别是，我们感兴趣的是，如何在这个广泛的结构的多样性 一系列化合物影响它们相互作用的能力，即，结合并 然后被近端小管细胞中的转运蛋白转运， OC跨上皮转运和细胞内蓄积的能量学 这些化合物。我们提出的研究与完整的肾小管，培养 细胞和从兔肾分离的亚细胞膜部分将 联合收割机传统的放射性示踪剂技术和新的光学方法， 测量运输。这里概述的实验将测试几个 假设提出，一般来说，（a）有一个系统的 结合效力与随后转运之间的关系 （B）OC转运蛋白的几种底物的综合活性 管腔和管周OC转运蛋白导致一些 OC和其他物质的重吸收;以及（c） 积累的OC被隔离在一个内体衍生的群体中， 胞内膜囊泡。通过了解 与肾脏转运和蓄积相关的机制 我们希望开发出第一个预测模型， 跨上皮肾OC转运途径特异性，并提供 第一个明确的测试在完整的肾小管目前的建议， OC通过近端小管转运。

Organic cations (and bases; collectively, "OCs") comprise a diverse array of molecules of physiological, pharmacological, and toxicological relevance. The transport processes in the kidney, particularly in the proximal tubule, play a major role in regulating levels of these compounds in the body. We seek an understanding of the mechanisms by which organic cations enter, leave, and are accumulated within renal calls. In particular, we are interested in how the diverse structures of this broad array of compounds influence their ability to interact, i.e., bind to and then be translocated by, transporters in proximal tubule cells, and in the energetics of transepithelial OC transport and intracellular accumulation of these compounds. Our proposed studies with intact tubules, cultured cells, and subcellular membrane fractions isolated from rabbit kidney will combine traditional radiotracer techniques and novel optical methods for measuring transport. The experiments outlined here will test several hypotheses proposing, in general, that: (a) there is a systematic relationship between efficacy of binding and subsequent transport of substrates by OC transporters; (b) the integrated activity of the several luminal and peritubular OC transporters results in the secretion of some OCs and the reabsorption of others; and (c) a substantial fraction of accumulated OCs is sequestered within an endosomally-derived population of intracellular membrane vesicles. Through an understanding of the mechanisms associated with the renal transport and accumulation of xenobiotic OCs we expect to develop the first predictive model for the specificity of a transepithelial renal OC transport pathway and provide the first definitive tests in intact tubules of current proposals for how OCs are transported by the proximal tubule.