Genomes and Genes
GROWTH FACTORS AND INFLAMMATORY BOWEL DISEASE
Principal Investigator: PAULINE LUND
Affiliation: University of North Carolina
Abstract: 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
- 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..These effects appear to be mediated in part by upregulation of HGF and downregulation of TGFbeta1. The data indicate that IGF-I can modulate the cytokine response to liver injury facilitating regeneration and reducing fibrosis...
- 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...