Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY/ABSTRACT OAT1 (SLC22A6) is the prototypical kidney organic anion (PAH) transporter. It is responsible for the transport of many drugs (eg. antibiotics, diuretics, antivirals, NSAIDs) and toxins (organic mercurials). We identified the transporter (as NKT); we also first published the Oat1 knockout (Oat1KO) and phenotypes. Our recent data indicates that OAT1 is central to many systemic and proximal tubule metabolic processes. Oat1KO metabolomics data indicates OAT1 may be the key in vivo transporter of uremic toxins accumulating in renal insufficiency and chronic kidney disease (CKD). Altering OAT1 function and/or expression may ameliorate the metabolic changes in states of compromised renal function. We hypothesize that the “true” physiological role of OAT1 is as a central component of a larger metabolic network involved in normal physiological and pathophysiological processes, and OAT1 exerts a modulatory effect on metabolic diseases (eg. uremic syndrome) via this network. We will define the OAT1-centered network in detail. Specifically: 1) We will construct the OAT1-centered metabolic network through metabolic reconstruction of transcriptomics and metabolomics data from the Oat1KO (using the systems biology techniques described). We should be able to clearly delineate the pathways by which OAT1 regulates normal metabolism by: a) overlaying ligand-based pharmacophore models (in-hand) upon this preliminary reconstructed OAT1-centered network, and b) testing of “hits” in wet lab transport assays. 2) We will then determine what role the validated OAT1-centered metabolic network (and key pathways within it) plays in the metabolic alterations of renal insufficiency using rodent subtotal nephrectomy models and human CKD metabolomics data. We seek to build a very detailed, fully validated, network of >200 metabolites and reactions that makes predictions that can be evaluated in pathophysiological models and disease states. In response to previous criticisms, we have revised the proposal, particularly with respect to the disease model—and included an expert collaborator from the UCSD O’Brien Center to help with the studies and interpretation. Although the project was considered ambitious, we emphasize the huge amount of preliminary data and “in house” expertise. The team of investigators has expertise in transport, metabolism, network biology, epidemiology of kidney disease, animal models, and statistical analysis of large data sets. This project will thus produce a validated detailed map of OAT1-centered metabolism in normal physiology and a diseased state, possibly the first of its kind for any multispecific “drug” transporter (Nigam, Nature Reviews Drug Discovery, 2015). The studies could lead to design of strategies for improving the metabolic abnormalities in CKD by affecting OAT1 function or expression; they will also help predict how OAT1-transported drugs affect metabolism in kidney disease.
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