Children with Inflammatory Bowel Disease (IBD) frequently develop an acquired growth hormone (GH) resistance. The inflammatory cytokine, Tumor Necrosis Factor alpha (TNF) has been implicated, although the underlying molecular mechanisms are not known. Consequences can include reductions in linear growth, muscle mass, bone density, and intestinal healing. We hypothesize that down regulation of the GH receptor (GHR) by TNF inhibits GH signaling in colitis. We will test this hypothesis in the following aims:
In Aim 1, we will determine whether GHR expression is reduced in children with IBD and in murine experimental colitis. The functional significance of TNF induced alterations in GHR expression will then be assessed in liver and colon cell lines. We will identify TNF response elements in the mouse GHR gene promoter, and characterize signal transduction mechanisms by which TNF regulates nuclear abundance and DNA binding of the cognate transcription factors.
In Aim 2, we will identify TNF dependent mechanisms of GH resistance in children with IBD and in murine experimental colitis. Abundance of the GHR relative to GH signaling and related parameters of growth, body composition, and colon histopathology will be determined folllowing administration of an anti-TNF antibody.
In Aim 3, we will determine whether beneficial effects of TNF neutralization in colitis require STATSb activation, by examining the effect of anti-TNF antibody administration to STATSb deficient mice with colitis. The overarching hypothesis of this work is that a global defect in GH dependent STATSb activation leads to growth failure and impaired mucosal healing in IBD. These studies will clarify the direct importance of reduced STATSb activation in altering GH signaling in colitis. If the proposed studies support the utility of TNF blockade in reversing GH resistance in colitis, these findings should translate into improved clinical therapies for children with IBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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Hamilton, Frank A
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Cincinnati Children's Hospital Medical Center
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