Major objectives of this research are to gain a better understanding of positive and negative mediators of inflammation induced intestinal fibrosis, an incurable complication of Crohn's disease (CD). Findings in animal models of acute colitis and in patients with CD indicate benefits of growth hormone (GH) therapy in CD but the documented fibrogenic effects of GH and insulin-like growth factor-I (IGF-I) which is induced by GH, support a hypothesis that GH therapy may exacerbate fibrosis in CD. Locally expressed IGF-I is up-regulated in myofibroblasts at sites fibrosis in CD and animal models of chronic intestinal inflammation implicating IGF-I as an endogenous mediator of fibrosis. Preliminary data support a hypothesis that suppressors of cytokine signaling (SOCS), may limit the fibrogenic actions of therapeutic or endogenous cytokines and growth factors in the inflamed intestine. Other data support a hypothesis that IGF-I interacts with another key cytokine, TNF-alpha to mediate collagen synthesis or proliferation in intestinal myofibroblasts, key cellular mediators of fibrosis in CD.
Specific aims are as follows:
Aim 1 will define if systemic GH increases fibrosis, circulating or locally expressed IGF-I during PG-PS induced enterocolitis. Cellular sites and levels of SOCS expression will be assessed to verify that SOCS2 or SOCS3 are expressed at in vivo sites that would permit them to limit fibrosis.
Aim 2 will define if IGF-I mediates GH action on collagen synthesis or proliferation in intestinal myofibroblasts and test whether SOCS limit GH or IGF-I action.
Aim 3 will define if mice with absolute or mesenchyme-specific SOCS2 deficiency show altered fibrosis, JGF-I induction or GH action during TNBS-colitis.
Aim 4 will define mechanisms if TNF-alpha has additive or synergistic effects with IGF-I, to induce collagen synthesis in intestinal myofibroblasts and if SOCS limit these effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047769-08
Application #
6879564
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
1995-09-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
8
Fiscal Year
2005
Total Cost
$255,655
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
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
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
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; 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

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