The major epithelial permeability barriers are controlled and regulated by a cascade of events triggered by homotypic and heterotypic cell/cell interactions and cell/extracellular matrix (ECM) interactions. Since starting this research, we have demonstrated that CD98, a type II membrane glycoprotein, is covalently linked to an amino-acid transporter in intestinal epithelial cells to form a heterodimer. In intestinal epithelia, the heterodimer is associated with ?1-integrin and intercellular adhesion molecular 1 (ICAM-1) to form a macromolecular complex in the basolateral membranes of polarized intestinal epithelial cells. The extracellular C-terminal domain of CD98 contains a PDZ-binding domain that has a role in ECM protein/protein interactions. Epithelial CD98 up-regulation is mediated by the pro-inflammatory cytokine interferon ? (IFN-?) during intestinal inflammation. Our overall hypothesis is that the macromolecular complex may control important functions such as cell/cell and cell/matrix interactions.
The first aim of this proposal is to investigate the functional effects of epithelial CD98 expression on in-vitro and in-vivo intestinal barrier function. Specifically, we will identify the specific molecular CD98 domains that affect intestinal epithelia permeability barriers. Second, we will investigate the role of CD98 in epithelial/T cell and epithelial/matrix interactions. Furthermore, we will identify the CD98 molecular domains that are responsible for these interactions. Finally, we will examine the role of CD98 that is expressed in T lymphocytes using an in-vivo approach. The project will involve a variety of biochemical, molecular, in vitro and in vivo approaches. In vitro experiments will use intestinal epithelial cell line Caco2-BBE and immune cell line Jurkat to investigate at the molecular and biochemical levels the expression/function of CD98 in intestinal inflammation. In vivo experiments will use mice that harbored a conditional CD98 gene and experimental colitis mice in order to confirm and develop the key information needed to design therapeutic strategies to ameliorate intestinal inflammatory conditions including IBD. Over one million adults and children in the U.S, suffer from inflammatory bowel disease. New therapeutic strategies based on a better understanding of the pathogenesis of IBD will improve the clinical care of patient with this disorder.

Public Health Relevance

Even though major advances have been made in the past decade with respect to understanding the genetics, environmental and immune dysregulation in IBD, the etiopathogenesis of IBD is poorly understood. It is envisaged that this investigation will define the molecular mechanisms underlying the functional role of CD98 in intestinal inflammation and initiate therapeutic strategies to ameliorate intestinal inflammatory conditions including IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071594-08
Application #
8291404
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Carrington, Jill L
Project Start
2005-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$282,986
Indirect Cost
$91,131
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; 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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