MOLECULAR ORGANIZATION OF RENAL ORGANIC CATION TRANSPORT

肾脏有机阳离子转运的分子组织

• 批准号: 6189837
• 负责人: STEPHEN H WRIGHT
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6189837
• 关键词: Xenopus oocyte; bioenergetics; cations; chemical kinetics; drug metabolism; human tissue; ion transport; laboratory rabbit; membrane transport proteins; molecular cloning; organic chemicals; renal tubular transport

Organic cations include a vast collection of pharmacologically important compounds. Indeed, drugs from a wide array of clinical classes-including antihistamines, skeletal muscle relaxants, antiarrythmics, and beta- adrenoceptor blocking agents-are organic cations (Ocs). The kidney plays a critical role in clearing these compounds from the body, thereby influencing their clinical effectiveness and posing the potential for undesirable interactions at the level of the excretory process. A general model of renal OC secretion has been in place for almost 20 years, but it does not include the molecular mechanisms of the processes involved and, therefore lacks the basis upon which to build a predictive model of the renal secretion of cationic drugs. The recent cloning of several 'candidate transporters' believed to play a role in renal OC transport )OCT1, OCT2, OCTN1, and OCTN2) makes possible development of a molecularly-based secretory model, provided that answers to several critical questions are obtained: (1) Where are these transporters expressed in the kidney; (2) How (mechanistically) do they contribute to OC secretion; and (3) What substrates are handled by each of the several (current) candidate transporters? Finally, (4) Can the ensemble behavior of these processes, based upon their measured characteristics, account for the secretory activity observed in proximal tubules? To answer these questions we have developed an experimental plan that will examine the above listed characteristics of the candidate transporters The approach involves comparison of results obtained with intact renal tubules with those obtained using single cloned transport proteins. The latter system permits examination of the properties of single transporters, while the former provides the only means to assess how the integrated activity of a suite of processes influences net transepithelial substrate movement. The cloned transporters will include the human orthologs of the four transporters and, also, the rabbit orthologs of each process. The latter set of observation will be used to validate use of the intact tubule systems we will employ to test a model of cationic drug secretion based upon the individual characteristics of each OC transporter. This study will be the first to offer an integrated view of the several processes that must work together to effect renal secretion of cationic drugs and thereby establish the necessary base for developing a therapeutically useful model of renal drug secretion.

有机阳离子包括大量重要的化合物。 实际上，来自广泛临床类别的药物-包括抗组胺药、骨骼肌松弛剂、抗心律失常药和β-肾上腺素受体阻断剂-都是有机阳离子（OCs）。 肾脏在从体内清除这些化合物方面起着关键作用，从而影响其临床有效性，并在排泄过程水平上造成潜在的不良相互作用。 肾脏OC分泌的通用模型已经存在近20年，但它不包括所涉及过程的分子机制，因此缺乏建立阳离子药物肾脏分泌预测模型的基础。 最近克隆了几种被认为在肾OC转运中起作用的“候选转运蛋白”（OCT 1、OCT 2、OCTN 1和OCTN 2），使得基于分子的分泌模型的发展成为可能，前提是获得了几个关键问题的答案：（1）这些转运蛋白在肾中的何处表达;（2）如何表达？（机械）他们有助于OC分泌;（3）什么基板处理的几个（目前）候选转运？最后，（4）这些过程的整体行为，基于它们的测量特征，能解释近端小管中观察到的分泌活动吗？为了回答这些问题，我们已经开发了一个实验计划，将检查上述列出的候选转运蛋白的特性。该方法涉及使用单个克隆转运蛋白获得的结果与完整肾小管的比较。 后一种系统允许检查单个转运蛋白的性质，而前者提供了唯一的手段来评估一套过程的综合活性如何影响净跨上皮基质运动。 克隆的转运蛋白将包括四种转运蛋白的人直系同源物，以及每个过程的兔直系同源物。 后一组观察结果将用于验证完整小管系统的使用，我们将采用该系统来测试基于每个OC转运蛋白的个体特征的阳离子药物分泌模型。 这项研究将是第一个提供一个综合的观点，必须共同努力，以影响阳离子药物的肾脏分泌的几个过程，从而建立必要的基础，开发一个治疗上有用的模型肾脏药物分泌。