RENAL ORGANIC CATION--SPECIFICITY AND ENERGETICS

有机阳离子(和碱；统称为“OCS”)组成了不同的阵列 生理、药理和毒理的分子 关联性。肾脏的转运过程，特别是在肾脏 近端小管在调节这些化合物的水平方面起着主要作用。 在身体里。我们寻求对有机物质 阳离子进入、离开，并在肾呼叫内积累。在……里面 特别是，我们感兴趣的是这个宽广的 化合物的排列影响其相互作用的能力，即结合和 然后被近端小管细胞中的转运蛋白转运，并在 跨上皮OC转运和细胞内蓄积的能量学 这些化合物中。我们建议对培养的完整小管进行研究 细胞，以及从兔肾中分离出的亚细胞膜部分 结合传统的放射性示踪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 一般而言，提出的假设是：(A)有系统的 结合效率与后续转运的关系 有机碳转运蛋白的底物；(B)几个 管腔和管周OC转运蛋白导致某些 以及(C)相当一部分 累积的OCS被隔离在由内脏派生的 细胞内膜囊泡。通过对以下内容的理解 与肾脏转运和蓄积有关的机制 异种生物OCS我们希望开发出第一个预测模型 跨上皮肾OC转运途径的特异性并提供 第一次在完整的小管中进行决定性的测试，目前关于如何 OCs由近端小管运输。

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.