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 21-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 3 (IFN-3) 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 #
7R01DK071594-07
Application #
8400697
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Carrington, Jill L
Project Start
2005-07-01
Project End
2013-06-30
Budget Start
2011-11-30
Budget End
2012-06-30
Support Year
7
Fiscal Year
2011
Total Cost
$277,230
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
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
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
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
Zhang, Mingzhen; Collins, James F; Merlin, Didier (2016) Do ginger-derived nanoparticles represent an attractive treatment strategy for inflammatory bowel diseases? Nanomedicine (Lond) 11:3035-3037
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, 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

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