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.

Public Health Relevance

Development of colitis-associated cancer (CAC) in patients suffering from UC is one of the best clinically characterized examples of an association between intestinal inflammation and carcinogenesis. Experiments outlined in this proposal will study the role of PepT1 in initiating and perpetuating intestinal colitis and consequently participate to the development of colitis associated cancer. Furthermore, using nanotechnology approaches, we will investigate the targeting of PepT1 for treatment of intestinal inflammation and colitis associated cancer. 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. The VA IBD patients have a much higher rate of colorectal cancer compared to the general population. 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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002526-01
Application #
8722663
Study Section
Gastroenterology (GAST)
Project Start
2014-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
City
Decatur
State
GA
Country
United States
Zip Code
30033
Xiao, Bo; Ma, Lijun; Merlin, Didier (2017) Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy. Expert Opin Drug Deliv 14:65-73
Titus, Jitto; Viennois, Emilie; Merlin, Didier et al. (2017) Minimally invasive screening for colitis using attenuated total internal reflectance fourier transform infrared spectroscopy. J Biophotonics 10:465-472
Xiao, Bo; Xu, Zhigang; Viennois, Emilie et al. (2017) Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis. Mol Ther 25:1628-1640
Chen, Qiubing; Si, Xiaoying; Ma, Lijun et al. (2017) Oral delivery of curcumin via porous polymeric nanoparticles for effective ulcerative colitis therapy. J Mater Chem B 5:5881-5891
Xiao, Bo; Ma, Panpan; Ma, Lijun et al. (2017) Effects of tripolyphosphate on cellular uptake and RNA interference efficiency of chitosan-based nanoparticles in Raw 264.7 macrophages. J Colloid Interface Sci 490:520-528
Zhang, Mingzhen; Xiao, Bo; Wang, Huan et al. (2016) Edible Ginger-derived Nano-lipids Loaded with Doxorubicin as a Novel Drug-delivery Approach for Colon Cancer Therapy. Mol Ther 24:1783-1796
Zhang, Yuchen; Viennois, Emilie; Zhang, Mingzhen et al. (2016) PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis. Sci Rep 6:27119
Zhang, Mingzhen; Xu, Changlong; Wen, Liuqing et al. (2016) A Hyaluronidase-Responsive Nanoparticle-Based Drug Delivery System for Targeting Colon Cancer Cells. Cancer Res 76:7208-7218
Viennois, Emilie; Ingersoll, Sarah A; Ayyadurai, Saravanan et al. (2016) Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model. Cell Mol Gastroenterol Hepatol 2:340-357
Xiao, Bo; Zhang, Zhan; Viennois, Emilie et al. (2016) Combination Therapy for Ulcerative Colitis: Orally Targeted Nanoparticles Prevent Mucosal Damage and Relieve Inflammation. Theranostics 6:2250-2266

Showing the most recent 10 out of 14 publications