New Targets for Regulating Drug/Xenobiotic Transporter OAT

项目摘要 有机阴离子转运蛋白（OAT）介导多种物质的吸收、分布和排泄 环境毒素和临床上重要的药物，包括抗癌药物，抗病毒药物， 利尿剂、抗生素、抗高血压药和抗炎药。OAT在哺乳动物中大量表达， 肾脏肝脏大脑和胎盘这些器官中的OAT功能障碍显著有助于肾脏， 肝脏、神经系统和胎儿毒性和疾病。尽管发挥着如此重要的作用，但如何发挥作用，在什么级别发挥作用， 运输者受到何种程度的管制是尚待回答的重要问题。在这 我们会探讨两个新目标，借以规管审裁处的活动： 去泛素化酶和蛋白酶体。提出了三个具体目标。在具体目标I中，我们将确定 调节OAT在培养细胞和组织中运输的不同步骤的特异性去泛素化酶 切片在具体目标II中，我们将评估蛋白酶体抑制在OAT介导的药物治疗中的作用。 在培养的细胞中运输。在具体目标III中，我们将评估生理和病理生理 蛋白酶体抑制在动物中OAT介导的药物转运中的相关性。联合入路 生物化学，分子生物学，细胞生物学和生理学将被用于拟议的 在培养细胞、组织切片和动物身上的研究。了解去泛素化酶的作用， 蛋白酶体对OAT的调控是药物转运领域的一个新的研究热点，将产生重大的影响 关于未来设计旨在最大限度地提高治疗效果和最大限度地减少毒性的策略，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.