Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD). Both diseases involve cycles of mucosal damage requiring mucosal restitution or regeneration to restore bowel function. In contrast to UC, CD is associated with transmural inflammation and fibrogenic complications, typified by submucosal granulomas altered mesenchymal cell proliferation and increased collagen deposition. Insulin- like growth factor I (IGF-I) expression is elevated in areas of fibrosis in bowel of animal models of chronic IBD. Expression of IGF-I and the related IGF-II is increased in involved bowel of patients with CD. IGFs prone proliferation of intestinal mesenchymal cells in vitro and intestinal epithelial cells in vitro and in vivo. Proposed studies will test the following hypotheses: 1. Phenotypically modified smooth muscle (SM) cells and/or fibroblasts (myofibroblasts) underlie fibrogenic complications of CD. 2. IGFs play an integral role in phenotypic modification or clonal expansion of the modified intestinal mesenchymal cells during development of fibrosis in CD. 3. Cytokines and/or extracellular matrix components within inflamed/fibrotic bowel of patients with CD induce IGF expression by intestinal mesenchymal cells or modulate IGF responsiveness by effects on IGF receptors or IGF binding proteins (IGFBPs). To test these hypotheses:
Aim 1 will elucidate the precise mesenchymal cell types that express IGF-I and IGF-II and show increased collagen deposition in inflamed or fibrotic regions of bowel from patients with CD.
Aim 2 will analyze cultured human intestinal smooth muscle cells and fibroblasts/myofibroblasts: a) to test IGF effects on proliferation, collagen deposition and phenotype in normal cells, b) to test effects of cytokines or extracellular matrix from inflamed/fibrotic bowel on IGF expression, phenotype and IGF responsiveness of normal cells and c) to examine whether cells from patients with CD show altered IGF expression or responsiveness compared with cells from patients with UC or noninflammatory bowel disease.
Aim 3 will use GH, IGF-I and IGFBP 1 transgenic mice (mice with inducible overexpression of IGFBP 1 a natural inhibitor of IGF-l action) to define in vivo effects of altered IGF-I production or action on susceptibility, course, severity and histopathology of experimental bowel inflammation and fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK047769-01A1
Application #
2147609
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1995-09-01
Project End
1999-06-30
Budget Start
1995-09-01
Budget End
1996-06-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Ding, Shengli; Blue, Randall E; Moorefield, Emily et al. (2017) Ex Vivo and In Vivo Noninvasive Imaging of Epidermal Growth Factor Receptor Inhibition on Colon Tumorigenesis Using Activatable Near-Infrared Fluorescent Probes. Mol Imaging 16:1536012117729044
Koblansky, A Alicia; Truax, Agnieszka D; Liu, Rongrong et al. (2016) The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. Cell Rep 14:2562-75
Ding, Shengli; Blue, Randal E; Morgan, Douglas R et al. (2014) Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models. Inflamm Bowel Dis 20:363-77
Hamilton, Kathryn E; Tétreault, Marie-Pier; Lund, P Kay (2013) Opportunities and challenges for women PhD investigators in gastrointestinal research. Gastroenterology 145:266-71
Van Landeghem, Laurianne; Santoro, M Agostina; Krebs, Adrienne E et al. (2012) Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation. Am J Physiol Gastrointest Liver Physiol 302:G1111-32
Ding, Shengli; Eric Blue, Randall; Chen, Yijing et al. (2012) Molecular imaging of gastric neoplasia with near-infrared fluorescent activatable probes. Mol Imaging 11:507-15
Ding, Shengli; Walton, Kristen L W; Blue, Randall Eric et al. (2012) Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen ?1(I)-promoter-GFP reporter mice. PLoS One 7:e42568
Bortvedt, Sarah F; Lund, P Kay (2012) Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors. Curr Opin Gastroenterol 28:89-98
Ding, Shengli; Lund, Pauline K (2011) Role of intestinal inflammation as an early event in obesity and insulin resistance. Curr Opin Clin Nutr Metab Care 14:328-33
Azcárate-Peril, M Andrea; Sikes, Michael; Bruno-Bárcena, José M (2011) The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol 301:G401-24

Showing the most recent 10 out of 27 publications