New Targets for Regulating Drug/Xenobiotic Transporter OAT

项目摘要 有机阴离子转运体(燕麦)调节多种物质的吸收、分布和排泄。 环境毒素，以及临床重要药物，包括抗癌药物，抗病毒药物， 利尿剂、抗生素、抗高血压药和消炎药。燕麦丰富地表达在 肾脏、肝脏、大脑和胎盘。这些器官中的燕麦功能障碍对肾脏有很大的贡献， 肝脏、神经和胎儿毒性和疾病。尽管扮演着如此重要的角色，但如何以及在什么级别和 运输商在多大程度上受到监管是有待回答的重要问题。在这 作为应用，我们将探索两个新的目标，通过这些目标可以调节燕麦片的活动： 去泛素酶和蛋白酶体。概述了三个具体目标。在具体目标一中，我们将确定 调节燕麦在培养细胞和组织中转运的不同步骤的特定脱泛素酶 切片。在特定的目标2中，我们将评估蛋白酶体抑制在燕麦蛋白介导的药物中的作用 在培养细胞中的运输。在特定目标III中，我们将评估生理和病理生理学 蛋白酶体抑制与燕麦蛋白介导的动物药物转运的相关性。综合方法 生物化学、分子生物学、细胞生物学和生理学将被应用于建议的 在培养细胞、组织切片和动物身上的研究。了解去泛素酶和泛素酶的作用 蛋白酶体在燕麦中的调节作用，这是药物转运领域的一个新焦点，将产生重大影响 关于未来旨在最大限度地提高治疗效果和最大限度地减少毒性的战略的设计，以及 将允许深入了解肾脏、肝脏、神经和胎儿的分子、细胞和临床基础 毒性和疾病。

Project Summary Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-cancer drugs, anti-viral agents, diuretics, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are abundantly expressed in kidney, liver, brain, and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological, and fetal toxicity and disease. Despite such a vital role, how and at what level and to what extents the transporters are regulated are important questions remain to be answered. In this application, we will explore two new targets, through which OAT activity can be regulated: deubiquitinases and proteasomes. Three Specific Aims are outlined. In Specific Aim I, we will identify the specific deubiquitinases that modulate distinct steps in OAT trafficking in cultured cells and in tissue slices. In Specific Aim II, we will assess the role of proteasomal inhibition in OAT-mediated drug transport in cultured cells. In Specific Aim III, we will evaluate the physiological and pathophysiological relevance of proteasomal inhibition in OAT-mediated drug transport in animals. Combined approaches of biochemistry, molecular biology, cell biology, and physiology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the roles of deubiquitinases and proteasomes in the regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.