GROWTH FACTORS AND INFLAMMATORY BOWEL DISEASE

Summary

Principal Investigator: PAULINE LUND
Affiliation: University of North Carolina
Country: USA
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

Top Publications

  1. doi Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models
    Shengli 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
  2. pmc Molecular imaging of gastric neoplasia with near-infrared fluorescent activatable probes
    Shengli 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
  3. pmc Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen α1(I)-promoter-GFP reporter mice
    Shengli 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
  4. pmc Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation
    Laurianne 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
  5. pmc Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria
    M 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
  6. pmc Suppressor of cytokine signaling 3 (SOCS3) is not an independent biomarker of colorectal adenoma risk
    Kathryn 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
  7. pmc Themes in fibrosis and gastrointestinal inflammation
    Claudio 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
  8. pmc Role of intestinal inflammation as an early event in obesity and insulin resistance
    Shengli 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
  9. pmc Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells
    Kathryn 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
  10. pmc Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors
    Sarah 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

Scientific Experts

  • Claudio Fiocchi
  • Shengli Ding
  • P Kay Lund
  • Kathryn E Hamilton
  • James G Simmons
  • Laurianne Van Landeghem
  • Arianne L Theiss
  • Pauline K Lund
  • Randall Eric Blue
  • Scott T Magness
  • Pauline Kay Lund
  • Sarah F Bortvedt
  • M Andrea Azcarate-Peril
  • Douglas Morgan
  • Brooks Scull
  • Howard Zhang
  • S Sanz
  • Shira Fruchtman
  • Douglas R Morgan
  • Randal E Blue
  • Adam D Gracz
  • Brooks P Scull
  • Amanda T Mah
  • Kristen L W Walton
  • Yijing Chen
  • M Agostina Santoro
  • Adrienne E Krebs
  • Kirk K McNaughton
  • Kirk Macnaughton
  • Jeffrey J Dehmer
  • Kirk McNaughton
  • Anthony Pease
  • Jody L Gookin
  • Derek M Foster
  • Sheila K Jacobi
  • Stephen H Stauffer
  • Maria B Cadenas
  • Maria R Stone
  • Robert S Sandler
  • Temitope O Keku
  • Joseph A Galanko
  • Nicole Ramocki
  • Gerald Cecil
  • Adam Burkholder
  • J A Fagin
  • J B Pucilowska
  • Carmen Z Michaylira
  • P K Lund
  • Bo Liu
  • J Prieto
  • R Balfour Sartor
  • J G Simmons
  • Denise M Ney
  • Christian Jobin
  • C R Fuller
  • S Liu
  • Christopher J Greenhalgh
  • A Pardo
  • D A Brenner
  • Megan E Miller
  • M L Martinez-Chantar
  • C Randall Fuller
  • C M Rodríguez-Ortigosa

Detail Information

Publications16

  1. doi Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models
    Shengli 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
    ....
  2. pmc Molecular imaging of gastric neoplasia with near-infrared fluorescent activatable probes
    Shengli 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...
  3. pmc Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen α1(I)-promoter-GFP reporter mice
    Shengli 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...
  4. pmc Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation
    Laurianne 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...
  5. pmc Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria
    M 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...
  6. pmc Suppressor of cytokine signaling 3 (SOCS3) is not an independent biomarker of colorectal adenoma risk
    Kathryn 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...
  7. pmc Themes in fibrosis and gastrointestinal inflammation
    Claudio 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...
  8. pmc Role of intestinal inflammation as an early event in obesity and insulin resistance
    Shengli 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...
  9. pmc Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells
    Kathryn 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...
  10. pmc Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors
    Sarah 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...
  11. ncbi Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells
    Shira 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
    ....
  12. ncbi Growth hormone reduces the severity of fibrosis associated with chronic intestinal inflammation
    Arianne 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...
  13. ncbi Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2
    Arianne 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...
  14. pmc Biochromoendoscopy: molecular imaging with capsule endoscopy for detection of adenomas of the GI tract
    Howard 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...
  15. pmc Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury
    S 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...