Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the digestive tract. The etiology of IBD remains poorly understood. Colorectal cancer is a life-threatening complication of both ulcerative and Crohn's colitis. The present application seeks to extend the findings of our previous studies, which showed that CD98 plays an important role in coordination of intestinal epithelial events. Such events include cell adhesion/polarity, amino acid transport, and direct binding of molecules to cell surfaces. Studies by our group have shown that CD98 expression plays a role in the pathogenesis of IBD. Our overall hypothesis is that colonic CD98 plays a critical role in initiating and perpetuating intestinal colitis. The initial aim of this proposal is to investigate the role played by interaction of CD98 with bacteria in terms of the loss of intestinal barrier function. The second specific aim is to investigate the role played by CD98 in upregulation of colonic mucosal activities including epithelial cell differentiation/polarization that may, in turn, affect intestinal barrier function. Finally, we will explore whether knockdown of CD98 expression, using a targeted nanotechnological approach, reduces the extent of colitis and colitis-associated cancer. The proposed project will use a variety of biochemical, molecular, nanotechnological, ex vivo, and in vivo techniques. We expect that we will develop therapeutic strategies, based on manipulation of CD98 expression in the colon, to reduce colitis and to inhibit development of colitis-associated cancer. More than one million adults and children in the United States suffer from IBD and complications of the condition, such as colitis-associated cancer. New therapeutic strategies based on a better understanding of IBD pathogenesis will improve the clinical care of such patients.

Public Health Relevance

Factors implicated in the pathophysiology of intestinal inflammation include a defect in intestinal epithelial barrier function, an abnormal immune response, and activities of the gut microbiota. It has been shown that colon mucosal CD98 is upregulated in IBD patients and in mice with active colitis. In the present proposal, we suggest that upregulation of colonic mucosal CD98 interacts with gut microbial activities and an abnormal immune response to initiate intestinal inflammation. In addition, we will investigate the effect of intestinal epithelial CD98 expression on epithelial cell differentiation/polarization tha may, in turn, influence intestinal barrier function. As CD98 plays an important role in regulation of cellular homeostasis and immunity, modulation of CD98 expression and/or function represents a promising therapeutic strategy for the treatment and prevention of colitis and colitis-associated cancer. We will manipulate CD98 expression in experimental disease models using advanced biotechnological techniques including nanotechnological approaches developed in our laboratory.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK071594-09A1
Application #
8687780
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30302
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
Titus, Jitto; Viennois, Emilie; Merlin, Didier et al. (2016) Minimally invasive screening for colitis using attenuated total internal reflectance fourier transform infrared spectroscopy. J Biophotonics :
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; Ma, Panpan; Viennois, Emilie et al. (2016) Urocanic acid-modified chitosan nanoparticles can confer anti-inflammatory effect by delivering CD98 siRNA to macrophages. Colloids Surf B Biointerfaces 143:186-93
Zhang, Mingzhen; Viennois, Emilie; Prasad, Meena et al. (2016) Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. Biomaterials 101:321-40
Xiao, Bo; Ma, Panpan; Ma, Lijun et al. (2016) 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
Viennois, Emilie; Merlin, Didier; Gewirtz, Andrew T et al. (2016) Dietary emulsifier-induced low-grade inflammation promotes colon carcinogenesis. Cancer Res :
Xiao, Bo; Si, Xiaoying; Zhang, Mingzhen et al. (2015) Oral administration of pH-sensitive curcumin-loaded microparticles for ulcerative colitis therapy. Colloids Surf B Biointerfaces 135:379-85

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