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 #
5R01DK071594-06
Application #
8094307
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Carrington, Jill L
Project Start
2005-07-01
Project End
2011-08-15
Budget Start
2011-07-01
Budget End
2011-08-15
Support Year
6
Fiscal Year
2011
Total Cost
$1
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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

Showing the most recent 10 out of 71 publications