Regulation of Drug/Xenobiotic Transporter OAT by Ubiquitination

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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.