After massive small bowel resection (SBR), the remaining intestine compensates by a critical process termed adaptation. Adaptation is largely a mitogenic signal for increased enterocyte proliferation, thus generating taller villi, and greater bowel caliber and length. While the mechanism for resection-induced enterocyte proliferation is presently unknown, we have established that epidermal growth factor receptor (EGFR) signaling is critical. Using p21waf1/cip1-null mice, we determined that proliferation was paradoxically abolished after SBR in the absence of this cyclin dependent kinase inhibitor. As an extension of these observations, we propose the global hypothesis that EGFR signaling regulates the expression of p21 to initiate enterocyte proliferation after SBR. To test this hypothesis, our aims are: 1) Delineate the effects of SBR and EGFR manipulations on intestinal p21 expression. Laser capture microdissection (LCM) microscopy wilt be employed to establish a temporal, regional, and enterocyte-specific expression of p21 mRNA and protein along the crypt-villus axis after SBR. Both in vivo and in vitro models of adaptation will be studied under conditions of EGFR stimulation and inhibition. 2) Determine the mechanism for EGFR regulation of p21. To test the hypothesis that EGFR governs p21 expression via STAT, we will elucidate STAT expression and activation after SBR in vivo and in vitro. We will then delineate p21 expression during adaptation in vitro after inhibition of STAT and in vivo in STATl-null mice. 3) Determine the mechanism for blocked postresection proliferation in p21-null mice.
This aim will test the hypothesis that postresection proliferation is prevented in p21-null mice because of compensatory increased expression of p27kip1. A temporal and cell compartment profile of P27 expression will be determined in p21-null mice. The magnitude of adaptation will then be elucidated in p27-null and p21/p27 double-null mice. These studies will contribute substantially toward an enhanced understanding of critical early signaling pathways involved in the regulation of adaptation. This information is fundamental toward the future development of safe and effective clinical therapy designed to amplify this important process.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Surgery and Bioengineering Study Section (SB)
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Hamilton, Frank A
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Cincinnati Children's Hospital Medical Center
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Warner, Brad W (2016) The Pathogenesis of Resection-Associated Intestinal Adaptation. Cell Mol Gastroenterol Hepatol 2:429-438
Warner, Brad W (2013) Adaptation: paradigm for the gut and an academic career. J Pediatr Surg 48:20-6
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
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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