Role of PepT1 in Intestinal Inflammation

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DESCRIPTION (provided by applicant): PepT1 is a member of the Proton Oligopeptide Transporter (POT) superfamily. PepT1 is well known to transport di/tripeptides, but not free amino acids or peptides with more than three amino acid residues. It is also well recognized that PepT1 is mostly expressed in epithelial cells of the small intestine and is present at low levels, or not at all, in such cells of the normal lare intestine. When we initiated our studies on PepT1, no known human pathology was associated with the transporter. Since the inception of our research, we have demonstrated that the human intestinal di- and-tri-peptide transporter, hPepT1, which is expressed in inflamed but not non-inflamed colonic epithelial cells, mediates the transport of small pro-inflammatory bacterial peptides such as formyl-Met-Leu-Phe (fMLP), muramyl dipeptide (MDP) and L-Ala- -D-Glu-meso-DAP (Tri- DAP), into the cytosol of colonic epithelial cells. Once in the cytosol, these small bacterial peptides can interact with members of the Nucleotide Binding Site-Leucine-Rich Repeat (NBS-LRR) family of intracellular receptors and initiate intestinal inflammatory responses. Importantly it has been shown (by another group that extensively cited our work) that a PepT1 polymorphism is associated with IBD. Overall, our studies have revealed that PepT1 may be associated with the pathogenesis of intestinal bowel disease (IBD) in humans. Our overall hypothesis is that colonic PepT1 plays a critical role in initiating and perpetuating intestinal colitis and consequently participate to the development of colitis associated cancer. The initial aim of this proposal is to investigate the PepT1-NOD2 signaling pathway(s) in colitis associated cancer. Second, we will explore the role of colonic PepT1 expression in weakness colonic barrier function and affecting wound healing that may an important determinant of colorectal cancer development in IBD. Finally, using nanotechnology approaches, we will investigate the targeting of PepT1 for treatment of intestinal inflammation and colitis associated cancer. It is envisaged that the planned work will identify the molecular mechanisms underlying the functional role of PepT1 in colitis associated cancer and allow development of therapeutic strategies targeting intestinal inflammatory conditions. Impact on Veterans Health care: Over one million adults in the US, including members of the VA population, suffer from IBD, and about 50,000 new cases are diagnosed each year (according to the Crohn's and Colitis Foundation of America. The VA IBD patients have a much higher rate of colorectal cancer compared to the general population (2.9% vs. 0.1%; from National Center for Health Statistics data). Thus, attaining an understanding of the etiology of IBD and the relevant pathological mechanisms are major aims of research seeking to develop effective future treatments will directly benefit the veteran population.