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.
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.
|Viennois, Emilie; Baker, Mark T; Xiao, Bo et al. (2015) Longitudinal study of circulating protein biomarkers in inflammatory bowel disease. J Proteomics 112:166-79|
|Laroui, Hamed; Viennois, Emilie; Xiao, Bo et al. (2014) Fab'-bearing siRNA TNF?-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis. J Control Release 186:41-53|
|Xiao, Bo; Laroui, Hamed; Viennois, Emilie et al. (2014) Nanoparticles with surface antibody against CD98 and carrying CD98 small interfering RNA reduce colitis in mice. Gastroenterology 146:1289-300.e1-19|
|Xiao, Bo; Yang, Yang; Viennois, Emilie et al. (2014) Glycoprotein CD98 as a receptor for colitis-targeted delivery of nanoparticle. J Mater Chem B Mater Biol Med 2:1499-1508|
|Laroui, Hamed; Geem, Duke; Xiao, Bo et al. (2014) Targeting intestinal inflammation with CD98 siRNA/PEI-loaded nanoparticles. Mol Ther 22:69-80|
|Xiao, Bo; Laroui, Hamed; Ayyadurai, Saravanan et al. (2013) Mannosylated bioreducible nanoparticle-mediated macrophage-specific TNF-* RNA interference for IBD therapy. Biomaterials 34:7471-82|
|Laroui, Hamed; Rakhya, Poonam; Xiao, Bo et al. (2013) Nanotechnology in diagnostics and therapeutics for gastrointestinal disorders. Dig Liver Dis 45:995-1002|
|Viennois, Emilie; Chen, Fengyuan; Merlin, Didier (2013) NF-?B pathway in colitis-associated cancers. Transl Gastrointest Cancer 2:21-29|
|Viennois, Emilie; Chen, Fengyuan; Laroui, Hamed et al. (2013) Dextran sodium sulfate inhibits the activities of both polymerase and reverse transcriptase: lithium chloride purification, a rapid and efficient technique to purify RNA. BMC Res Notes 6:360|
|Charania, Moiz A; Laroui, Hamed; Liu, Hongchun et al. (2013) Intestinal epithelial CD98 directly modulates the innate host response to enteric bacterial pathogens. Infect Immun 81:923-34|
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