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 following administration of an anti-TNF antibody.
In Aim 3, we will determine whether beneficial effects of TNF neutralization in colitis require STAT5b activation, by examining the effect of anti-TNF antibody administration to STAT5b deficient mice with colitis. The overarching hypothesis of this work is that a global defect in GH dependent STAT5b activation leads to growth failure and impaired mucosal healing in IBD. These studies will clarify the direct importance of reduced STAT5b 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK068164-01A2
Application #
7047643
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Hamilton, Frank A
Project Start
2006-04-01
Project End
2010-12-31
Budget Start
2006-04-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$298,000
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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