This proposal describes a five year training program for the development of an academic career in Molecular Medicine, with a focus on the pharmacogenetics of renal transporters. The principal investigator (PI), who holds M.D. and Ph.D. degrees, and is residency-trained in Internal Medicine, has already initiated research on the molecular biology of renal organic anion and cation transporters (OATs and OCTs) in the laboratory of Dr. Sanjay Nigam, the proposed mentor, at the University of California, San Diego (UCSD). Dr. Nigam is a distinguished Physician-Scientist who has authored numerous influential studies on renal transporters as well as on kidney development. The program, which incorporates formal didactics as well as research training, will enhance the PI's skills in the areas of pharmacogenetics, bioinformatics, transcriptional regulation, and developmental biology. Research will focus on the transcriptional regulation of OATs and OCTs. These transporters are important components of the renal drug-excretion machinery, transporting antibiotics, non-steroidal anti-inflammatory drugs, and anti-hypertensives, among other important pharmaceuticals. As such, it is likely that variations (SNPs) in OAT and OCT genes contribute significantly to inter-individual differences in drug-handling capacity, a cause of much morbidity and mortality. As critical SNPs might lie in transcription-regulating as well as coding regions, delineation of the regulatory regions will be an essential step in correlating such variations with clinical phenotypes. However, there have been no investigations, as yet, of the transcriptional regulation of OATs and OCTs, a gap that our proposed studies aim to help fill.
Our specific aims are as follows: (1) We will employ cell culture models to characterize the regulatory regions of OATs and OCTs, using computational sequence analyses to prioritize elements to be tested for activity. (2) The onset of OAT and OCT expression in the kidney approximately coincides with the differentiation of the proximal tubule. We will therefore test the hypothesis that OAT and OCT expression is influenced by """"""""master"""""""" factors that are also key regulators of proximal tubulogenesis. (3) We will characterize the mechanisms underlying androgen regulation of OAT and OCT genes.
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