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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK064839-05
Application #
7252688
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2003-07-20
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$125,396
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Vallon, Volker; Rieg, Timo; Ahn, Sun Young et al. (2008) Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol 294:F867-73
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Kaler, Gregory; Truong, David M; Khandelwal, Akash et al. (2007) Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members. J Biol Chem 282:23841-53
Sweet, D H; Eraly, S A; Vaughn, D A et al. (2006) Organic anion and cation transporter expression and function during embryonic kidney development and in organ culture models. Kidney Int 69:837-45
Eraly, Satish A; Vallon, Volker; Vaughn, Duke A et al. (2006) Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem 281:5072-83
Kaler, Gregory; Truong, David M; Sweeney, Derina E et al. (2006) Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions. Biochem Biophys Res Commun 351:872-6

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