The focus of the current project is on the pharmacology and therapeutic potential of an amino acid transporter known as ATB0,+ (amino acid transporter B0,+). ATB0,+ transports neutral and cationic amino acids in an energy-dependent manner, driven by the combined transmembrane gradients of Na+ and Cl-, as well as membrane potential. Recent studies have uncovered a number of novel and exciting, but hitherto unsuspected, functional features of this transporter. ATB0,+ exhibits a unique expression pattern in the mammalian intestine where its expression is restricted to the colon and ileum. In addition to its role in amino acid transport, it also functions as a carnitine transporter, D-serine transporter, drug transporter, and prodrug transporter. This multi-faceted transport function of ATB0,+ makes it unique among the amino acid transporters. These interesting findings form the basis of the current project. Studies proposed under Specific Aim 1 will focus on the physiological functions of ATB0+ and their therapeutic relevance. One of the important outcomes of these studies will be the information regarding the role of ATB0,+ in the colonic absorption of bacteria-derived D-serine and the relevance of bacterial colonization of the colon to the expression of the transporter. Since D-serine is an important regulator of the N-methyl-D-aspartate receptor function, establishing the role of ATB0,+ in the absorption of bacteria-derived D-serine is critical to assess the potential influence of intestinal microbial flora on glutamatergic neurotransmission in the host. Studies proposed under Specific Aim 2 will focus on the potential of ATB0,+ as a Na+Cl-coupled transporter for a variety of therapeutic agents. There is convincing evidence to suggest that ATB0,+ can be exploited as an effective delivery system for structurally diverse drugs and prodrugs in the colon and lung. Establishing the utility of ATB0,+ as a drug transporter will open up a new avenue for enhancing the bioavailability and therapeutic potency of various drugs. The focus of Specific Aim 3 is on the pathological relevance of ATB0,+. Studies proposed under this specific aim will test the hypothesis that intestinal and colonic inflammation enhances the expression of ATB0,+ in the colon and ileum, with consequent increases in the absorption of arginine, carnitine, and D-serine. The results of these studies will have significant clinical implications because of the potential for alterations in nitric oxide production, carnitine homeostasis, and glutamatergic neurotransmission under pathological conditions associated with inflammation of the intestinal tract. Studies proposed under this specific aim will also explore the possibility that ATB0,+ is functionally coupled to nitric oxide synthases nNOS and/or iNOS via protein-protein interaction analogous to the established association between eNOS and the cationic amino acid transporter CAT1.
|Gupta, Naren; Prasad, Puttur D; Ghamande, Sharad et al. (2006) Up-regulation of the amino acid transporter ATB(0,+) (SLC6A14) in carcinoma of the cervix. Gynecol Oncol 100:8-13|
|Gupta, Naren; Miyauchi, Seiji; Martindale, Robert G et al. (2005) Upregulation of the amino acid transporter ATB0,+ (SLC6A14) in colorectal cancer and metastasis in humans. Biochim Biophys Acta 1741:215-23|
|Ganapathy, M E; Ganapathy, V (2005) Amino Acid Transporter ATB0,+ as a delivery system for drugs and prodrugs. Curr Drug Targets Immune Endocr Metabol Disord 5:357-64|
|Umapathy, Nagavedi S; Ganapathy, Vadivel; Ganapathy, Malliga E (2004) Transport of amino acid esters and the amino-acid-based prodrug valganciclovir by the amino acid transporter ATB(0,+). Pharm Res 21:1303-10|
|Hatanaka, Takahiro; Haramura, Masayuki; Fei, You-Jun et al. (2004) Transport of amino acid-based prodrugs by the Na+- and Cl(-) -coupled amino acid transporter ATB0,+ and expression of the transporter in tissues amenable for drug delivery. J Pharmacol Exp Ther 308:1138-47|