Trafficking and Regulation of Drug/Xenobiotic Transporter OAT

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DESCRIPTION (provided by applicant): The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti- inflammatories, and therefore is critical for the survival of mammalian species. Six OATs have been identified (OAT1, OAT2, OAT3, OAT4, OAT5, and OAT6) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through OATs. We have strong preliminary data to show that OATs are subjected to acute regulation by cellular signaling pathways and that such regulation is coupled to dynamic changes in OAT cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the mechanisms underlying this regulation are completely unknown. The major goal of this application is to determine the cellular and molecular mechanisms governing OAT1 trafficking, and to evaluate the physiological and pathophysiological relevance of this form of regulation. Four Specific Aims (SAs) are outlined. In SA-1, we will analyze basal and regulated OAT1 trafficking kinetics. In SA-2, we will dissect the pathways involved in OAT1 trafficking. In SA-3, we will identify the structural motifs in OAT1 sequence involved in their trafficking. In SA-4, we will evaluate the physiological and pathophysiological relevance of OAT1 trafficking in regulation of drug transport activity. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in tissue slices, and cultured cells. Understanding the trafficking and 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, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti- inflammatories, and therefore is critical for the survival of mammalian species. Six OATs have been identified (OAT1, OAT2, OAT3, OAT4, OAT5, and OAT6) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through OATs. We have strong preliminary data to show that OATs are subjected to acute regulation by cellular signaling pathways and that such regulation is coupled to dynamic changes in OAT cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the mechanisms underlying this regulation are completely unknown. The major goal of this application is to determine the cellular and molecular mechanisms governing OAT1 trafficking, and to evaluate the physiological and pathophysiological relevance of this form of regulation. Understanding the trafficking and 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.