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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068164-04
Application #
7565949
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
2009-01-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$283,571
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Denson, Lee A; McDonald, Scott A; Das, Abhik et al. (2017) Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants. Am J Perinatol 34:240-247
Willson, Tara A; Jurickova, Ingrid; Collins, Margaret et al. (2013) Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice. Inflamm Bowel Dis 19:512-25
Prosnitz, Aaron R; Leonard, Mary B; Shults, Justine et al. (2013) Changes in vitamin D and parathyroid hormone metabolism in incident pediatric Crohn's disease. Inflamm Bowel Dis 19:45-53
Willson, Tara A; Kuhn, Benjamin R; Jurickova, Ingrid et al. (2012) STAT3 genotypic variation and cellular STAT3 activation and colon leukocyte recruitment in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 55:32-43
D'Mello, Sharon; Trauernicht, Anna; Ryan, Anne et al. (2012) Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis. Inflamm Bowel Dis 18:236-45
Huff, Chad D; Witherspoon, David J; Zhang, Yuhua et al. (2012) Crohn's disease and genetic hitchhiking at IBD5. Mol Biol Evol 29:101-11
Samson, Charles M; Jurickova, Ingrid; Molden, Erin et al. (2011) Granulocyte-macrophage colony stimulating factor blockade promotes ccr9(+) lymphocyte expansion in Nod2 deficient mice. Inflamm Bowel Dis 17:2443-55
Denson, Lee A; Kim, Mi-Ok; Bezold, Ramona et al. (2010) A randomized controlled trial of growth hormone in active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 51:130-9
Thayu, Meena; Denson, Lee A; Shults, Justine et al. (2010) Determinants of changes in linear growth and body composition in incident pediatric Crohn's disease. Gastroenterology 139:430-8
Ahrens, Richard; Waddell, Amanda; Seidu, Luqman et al. (2008) Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. J Immunol 181:7390-9

Showing the most recent 10 out of 15 publications