Genomes and Genes
GROWTH FACTORS AND INFLAMMATORY BOWEL DISEASE
Principal Investigator: PAULINE LUND
Affiliation: University of North Carolina
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 1995-09-01 - 2009-03-31
more information: NIH RePORT
- Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis modelsShengli Ding
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, Vanderbilt University, Nashville, Tennessee
Inflamm Bowel Dis 20:363-77. 2014....
- Molecular imaging of gastric neoplasia with near-infrared fluorescent activatable probesShengli Ding
Department of Cell and Molecular Physiology and Division of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Mol Imaging 11:507-15. 2012..The cathepsin probe also detects hyperplastic lesions...
- Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen α1(I)-promoter-GFP reporter miceShengli Ding
Department of Cell and Molecular Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
PLoS ONE 7:e42568. 2012..Intestinal fibrosis is a major complication of Crohn's disease. The cellular and molecular basis of mucosal healing and intestinal fibrosis are not well defined and better understanding requires well characterized mouse models...
- Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiationLaurianne Van Landeghem
Department of Cellular and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599 7545, USA
Am J Physiol Gastrointest Liver Physiol 302:G1111-32. 2012..These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration...
- Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteriaM Andrea Azcarate-Peril
Department of Cell and Molecular Physiology and Microbiome Core Facility, University of North Carolina, Chapel Hill, NC, USA
Gut Microbes 2:234-43. 2011..and members of the Actinobacteria and Cyanobacteria in the pathogenesis of NEC in preterm piglets...
- Suppressor of cytokine signaling 3 (SOCS3) is not an independent biomarker of colorectal adenoma riskKathryn E Hamilton
Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, 130 Mason Farm Road, Chapel Hill, North Carolina 27599 7545, USA
BMC Res Notes 3:144. 2010..As SOCS3 has been shown to inhibit the actions of IL-6 and TNFalpha in the intestine, we hypothesized that decreased SOCS3 expression in normal mucosa may predispose to adenomas and thus increase risk for CRC...
- Themes in fibrosis and gastrointestinal inflammationClaudio Fiocchi
Dept of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195
Am J Physiol Gastrointest Liver Physiol 300:G677-83. 2011..This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease...
- Role of intestinal inflammation as an early event in obesity and insulin resistanceShengli Ding
Department of Cell and Molecular Physiology, Center for Gastrointestinal Biology and Disease University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 7574, USA
Curr Opin Clin Nutr Metab Care 14:328-33. 2011..To highlight recent evidence supporting a concept that intestinal inflammation is a mediator or contributor to development of obesity and insulin resistance...
- Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cellsKathryn E Hamilton
Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Mol Cancer Res 9:1718-31. 2011..Collectively, these studies show that IL-6- and TNFα-induced TNFR2 expression in colon cancer cells is mediated primarily by STAT3 and provide evidence that TNFR2 may contribute to the tumor-promoting roles of STAT3...
- Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factorsSarah F Bortvedt
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Curr Opin Gastroenterol 28:89-98. 2012..To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance...
- Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cellsShira Fruchtman
Dept of Cell and Molecular Physiology, CB 7545, University of North Carolina Chapel Hill, Chapel Hill, NC 27599 7545, USA
Am J Physiol Gastrointest Liver Physiol 289:G342-50. 2005....
- Growth hormone reduces the severity of fibrosis associated with chronic intestinal inflammationArianne L Theiss
Department of Cell and Molecular Pathology, The Univesity of North Carolina at Chapel Hill, 27599 7545, USA
Gastroenterology 129:204-19. 2005..We tested if GH treatment altered inflammation or fibrosis during chronic, experimental granulomatous enterocolitis...
- Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2Arianne L Theiss
Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
J Biol Chem 280:36099-109. 2005..TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation...
- Biochromoendoscopy: molecular imaging with capsule endoscopy for detection of adenomas of the GI tractHoward Zhang
Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Gastrointest Endosc 68:520-7. 2008..Near infrared fluorescent (NIRF) probes activated by biomarkers upregulated in adenomas (eg, cathepsin B) are potentially powerful tools to distinguish premalignant or malignant lesions from benign or inflammatory lesions...
- Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injuryS Sanz
Division of Hepatology and Gene Therapy, Clinica Universitaria and Medical School, Center for Applied Medical Research CIMA, University of Navarra, 31008, Pamplona, Spain
Gut 54:134-41. 2005..Insulin-like growth I (IGF-I) has been shown to stimulate HSCs proliferation in vitro, but it has been reported to reduce liver damage and fibrogenesis when given to cirrhotic rats...