Sunday, May 19, 2024
5/19/2024
DESCRIPTION (provided by applicant): The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of substances, including drugs, toxins, neurotransmitters, and environmental pollutants (xenobiotics). Four Oats have been identified (Oat1, Oat2, Oat3, and Oat4) and their expression has been detected in kidney and in the choroid plexus (CP) epithelium lining the ventricles of the brain. Thus, disruption of renal OAT function may significantly change the systemic toxicity of substrates and disruption of CP OAT function may decrease clearance of organic anions from the cerebrospinal fluid resulting in increased CNS toxicity and/or neurological dysfunction. Our long-term goal is to quantify the contribution of each OAT to the prevention of systemic, renal, hepatic, and CNS toxicity and disease. In order to correctly interpret data concerning individual OAT function, an accurate model of the transport system is essential. Indeed, recent work has resulted in reassignment of Oat3 within this model (see Preliminary Studies). The working hypotheses for this proposal are (1) the current model for the classical renal organic anion transport system incorrectly defines the role of Oat2 in the excretion of toxic organic anions, (2) disruption of individual OAT function leads to altered substrate distribution, excretion, and toxicity and (3) altered OAT function is the cause of some forms of CNS dysfunction. This project will advance these concepts through the following specific aims: SA#1) To test the hypothesis that the transporter Oat2 is a basolateral organic anion/dicarboxylate exchanger, SA#2) To test the hypothesis that Oat2-mediated transport contributes to the clearance of uremic toxins and neurotransmitter metabolites, SA#3) To test the hypothesis that knockout of the Oat3 gene affects the in vivo distribution and excretion of endogenous and xenobiotic organic anions. Elucidation of the pharmacokinetics and pharmacodynamics of individual OAT function has broad implications for understanding the molecular basis of systemic, renal, hepatic, and CNS toxicity, as well as interindividual variations in drug efficacy, disposition, and interaction (drug/drug and drug/food).
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