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 interactin 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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071594-10
Application #
8833273
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Greenwel, Patricia
Project Start
2005-07-01
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
10
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Viennois, Emilie; Pujada, Adani; Zen, Jane et al. (2018) Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol 8:731-760
Viennois, Emilie; Tahsin, Anika; Merlin, Didier (2018) Purification of Total RNA from DSS-treated Murine Tissue via Lithium Chloride Precipitation. Bio Protoc 8:
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
Titus, Jitto; Ghimire, Hemendra; Viennois, Emilie et al. (2018) Protein secondary structure analysis of dried blood serum using infrared spectroscopy to identify markers for colitis screening. J Biophotonics 11:
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
Ma, Lijun; Chen, Qiubing; Ma, Panpan et al. (2017) iRGD-functionalized PEGylated nanoparticles for enhanced colon tumor accumulation and targeted drug delivery. Nanomedicine (Lond) 12:1991-2006
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
Viennois, Emilie; Merlin, Didier; Gewirtz, Andrew T et al. (2017) Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. Cancer Res 77:27-40
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
Zhang, Mingzhen; Wang, Xiaoyu; Han, Moon Kwon et al. (2017) Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis. Nanomedicine (Lond) 12:1927-1943

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