Abstract

The loss of significant intestinal length results in substantial morbidity and mortality and is associated with multiple conditions including Crohn s disease, trauma, intestinal volvulus, and necrotizing enterocolitis. Adaptation is an important response of the remaining bowel consisting of hypertrophy, hyperplasia, and increased digestive and absorptive capacity. Epidermal growth factor (EGF) has been shown to enhance this response by an unknown mechanism(s). This proposal will test the hypothesis that adaptation is mediated by EGF and its enterocyte receptor (EGF-R). We have developed a model for massive (50 percent) small bowel resection (SBR) in the mouse to enable a direct study of the consequences of EGF/EGF-R gene manipulation during adaptation. Changes in intestinal EGF-R mRNA and protein expression and activity following SBR will be determined. Adaptation will be analyzed following SBR in the context of models for manipulation of the EGF/EGF-R axis. The EGF/EGF-R axis will be stimulated by administration of EGF, targeted intestinal overexpression of EGF and EGF-R in transgenic mice, and transgenic mice that overexpress TGFalpha (another ligand for the EGF-R). Models for EGF/EGF-R axis inhibition will include surgical removal of the major source of EGF production in the mouse (submandibular glands), administration of EGF-R protein tyrosine kinase inhibitors, and a strain of mouse harboring a defect of EGF-R signal transduction. We will test the hypothesis that the mechanism for enhanced adaptation by EGF/EGF-R axis stimulation is by increasing rates of enterocyte proliferation as well as reducing rates of programmed cell death (apoptosis). Enterocyte migration, differentiation, proliferation, and apoptosis will be determined following SBR and then studied in the context of models for EGF/EGF-R axis manipulation. Further understanding of the EGF/EGF-R axis is crucial toward the development of novel therapeutic strategies designed to enhance the intestinal adaptive response to massive intestinal loss.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053234-05
Application #
6489697
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Hamilton, Frank A
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
5
Fiscal Year
2002
Total Cost
$148,000
Indirect Cost

  Institution

Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229

  Publications

Warner, Brad W (2016) The Pathogenesis of Resection-Associated Intestinal Adaptation. Cell Mol Gastroenterol Hepatol 2:429-438
Rowland, Kathryn J; Choi, Pamela M; Warner, Brad W (2013) The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Semin Pediatr Surg 22:101-11
Warner, Brad W (2013) Adaptation: paradigm for the gut and an academic career. J Pediatr Surg 48:20-6
Leinicke, Jennifer A; Longshore, Shannon; Wakeman, Derek et al. (2012) Regulation of retinoblastoma protein (Rb) by p21 is critical for adaptation to massive small bowel resection. J Gastrointest Surg 16:148-55; discussion 155
Guo, Jun; Longshore, Shannon; Nair, Rajalakshmi et al. (2009) Retinoblastoma protein (pRb), but not p107 or p130, is required for maintenance of enterocyte quiescence and differentiation in small intestine. J Biol Chem 284:134-40
Qiu, Zhaohua; Longshore, Shannon W; Warner, Brad W et al. (2009) Murine functional liver mass is reduced following partial small bowel resection. J Gastrointest Surg 13:2176-82
Longshore, Shannon W; Nair, Rajalakshmi; Perrone, Erin E et al. (2009) p21(waf1/cip1) deficiency does not perturb the intestinal crypt stem cell population after massive small bowel resection. J Pediatr Surg 44:1065-71; discussion 1071
Taylor, Janice A; Martin, Colin A; Nair, Rajalakshmi et al. (2008) Lessons learned: optimization of a murine small bowel resection model. J Pediatr Surg 43:1018-24
Tantemsapya, Niramol; Meinzner-Derr, Jareen; Erwin, Christopher R et al. (2008) Body composition and metabolic changes associated with massive intestinal resection in mice. J Pediatr Surg 43:14-9
Martin, Colin A; Bernabe, Kathryn Q; Taylor, Janice A et al. (2008) Resection-induced intestinal adaptation and the role of enteric smooth muscle. J Pediatr Surg 43:1011-7

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