PepT1, which is a member of the proton oligopeptide transporter (POT) superfamily, is well known to transport di/tripeptides. Our group and others have shown that PepT1 is highly expressed in epithelial cells of the small intestine, but present at low or undetectable levels in such cells of the normal large intestine (1-8). We previously showed that the expression and transport activities of PepT1 contribute to colitis and colitis associated cancer (5, 9). More recently, we reported that the function of this membrane transporter is not restricted to its classical function as transporter of di-tripeptides. For example, we demonstrated that PepT1 expression helps maintain intestinal homeostasis by mediating intestinal miRNA expression/secretion (10, 48). Together, our prior studies revealed that PepT1 may be associated with intestinal homeostasis and implicated in various pathogeneses, including those of colitis and colitis associated cancer. Our novel overall hypothesis is that small intestinal PepT1 expression plays a critical role in maintaining intestinal homeostasis and in shaping the gut microbiota. The initial aim of this proposal is to demonstrate that a lack of small intestinal PepT1 expression shapes the gut microbiota into an anti-inflammatory microbiota that is implicated in preventing colitis and colitis associated cancer. We will then explore the effects of small intestinal PepT1 expression and consequently the intestinal miRNA dysregulation on the intestinal mucosal homeostasis. Finally, we will investigate how the microbiota is regulated by the expression/secretion of host miRNAs that depend on the expression of PepT1 in the small intestine, and we will define ways to manipulate the microbiome by administering specific miRNAs. We envisage that the planned work will identify the role played by small intestinal PepT1 expression plays a critical role in maintaining intestinal homeostasis and in shaping the gut microbiota. The proposed research will also facilitate the development of therapeutic strategies targeting intestinal inflammatory conditions.

Public Health Relevance

Overall, our proposal is conceptually novel in that it seeks to implicate a membrane transporter in essential pathophysiological functions that are not directly dependent on its transport activities. In addition, the proposed research will also facilitate the development of therapeutic strategies targeting intestinal inflammatory conditions, including colitis 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 (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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002526-06
Application #
9683776
Study Section
Gastroenterology (GAST)
Project Start
2014-07-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
824835805
City
Decatur
State
GA
Country
United States
Zip Code
30033
Han, Moon K; Baker, Mark; Zhang, Yuchen et al. (2018) Overexpression of CD98 in intestinal epithelium dysregulates miRNAs and their targeted proteins along the ileal villus-crypt axis. Sci Rep 8:16220
Yang, Chunhua; Zhang, Mingzhen; Merlin, Didier (2018) Advances in Plant-derived Edible Nanoparticle-based lipid Nano-drug Delivery Systems as Therapeutic Nanomedicines. J Mater Chem B 6:1312-1321
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
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
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
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, 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

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