Regulation of Drug/Xenobiotic Transporter OAT by Ubiquitination

描述(申请人提供)：有机阴离子转运体(OATS)调节临床重要药物的吸收、分配和排泄，包括抗HIV治疗药物、抗肿瘤药物、抗生素、抗高血压药物和抗炎药物。燕麦主要在肾脏、肝脏、脑和胎盘中表达。燕麦在这些器官中的功能障碍极大地导致了肾、肝、神经和胎儿的毒性和疾病。我们有新的初步数据表明，OAT3的表面表达和活性受到转运蛋白泛素化的控制。这一应用的目的是确定泛素化调控OAT3活性的细胞和分子机制，并评估这种调控的生理学和病理生理学相关性。概述了三个具体目标(SA)。在SA-I中，我们将确定OAT3泛素化的性质。在SA-II中，我们将评估泛素化在OAT3介导的药物转运中的作用。在SA-III中，我们将评估泛素化在OAT3介导的药物转运中的生理学和病理生理学相关性。生物化学和分子生物学的结合方法将被用于在培养细胞、组织切片和动物中进行拟议的研究。泛素化是药物转运领域的一个新热点，了解泛素化在燕麦调节中的作用，将对未来旨在最大化疗效和最小化毒性的策略的设计产生重大影响，并将使人们能够深入了解肾、肝、神经和胎儿毒性和疾病的分子、细胞和临床基础。 与公共健康相关：有机阴离子转运体(OAT)家族调节多种环境毒素和临床重要药物的吸收、分布和排泄。因此，了解燕麦的调节机制将对未来治疗策略的设计产生重大影响。

DESCRIPTION (provided by applicant): Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are mainly expressed in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. We have novel preliminary data to show that the surface expression and activity of OAT3 are controlled by the ubiquitination of the transporter. The goal of this application is to determine the cellular and molecular mechanisms governing the regulation of OAT3 activity by ubiquitination, and to evaluate the physiological and pathophysiological relevance of such regulation. Three Specific Aims (SAs) are outlined. In SA-I, we will identify the nature of OAT3 ubiquitination. In SA-II, we will assess the role of ubiquitination in OAT3-mediated drug transport. In SA-III, we will evaluate the physiological and pathophysiological relevance of ubiquitination in OAT3-mediated drug transport. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the role of ubiquitination 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. PUBLIC HEALTH RELEVANCE: The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs. Therefore, understanding the regulation of OATs will have significant impact on the future design of therapeutic strategies.