Intestinal adaptation is a critical, compensatory response to massive small bowel resection (SBR) and characterized by increased enterocyte turnover as gauged by elevated rages of both proliferation and apoptosis. The significance of apoptosis to the magnitude of adaptation was revealed during the previous funding cycle of this grant as amplified adaptation was observed when apoptosis was actively inhibited. While the mechanisms(s) for elevated apoptosis after SBR is presently unknown, we have established that this response is regulated by epidermal growth factor receptor (EGFR) signaling and requires expression of the proapototic Bcl02 family member Bax and the transcription factor signal transducer and activator of transcription (STAT)-1. As an extension of these key observations, we propose the global hypothesis that EGFR signaling modulates the expression and activity of Bax to regulate resection-induced apoptosis. To test this hypothesis our aims are: 1) Determine the role for STAT-1 in the regulation of Bax expression during intestinal adaptation. STAT-1 expression and activity will be determined in the ileum after SBR as well as in cell culture following induction of apoptosis. The effect of STAT-1 deficiency on Bax expression and apoptosis will be measured and putative STAT-1 binding sites on Bax promoter will be investigated. 2) Determine the role of p38alpha mitogen-activated protein kinase (MAPK) as modulator of Bax activity during resection induced adaptation. A temporal and spatial profile of p38 expression/activity and Bax activation will be recorded after SBR in mice and complementary in vitro models of apoptosis. The effect of conditional, intestine-specific deletion of p38 expression on Bax activity and apoptosis will be determined after SBR. 3) Determine the mechanism for EGFR regulation of Bax expression and activity. The effect of enhanced or disrupted EGFR signaling on STAT-1 and p38 activation and expression will be recorded. The effect of attenuated STAT-1 or p38 expression in the context of EGFR inhibition on apoptosis and Bax activity and expression will be determined. The proposed studies in this application will identify the most relevant signaling pathway to direct apoptosis after massive SBR. A thorough understanding of the precise mechanism for induction of apoptosis is fundamental for bench-to-bedside translation of therapeutic targets intended to maximally stimulate regrowth of the intestinal mucosa in response to massive intestinal loss.

Public Health Relevance

Following massive intestinal loss, the remaining bowel attempts to grow back to compensate. If this response is incomplete, the patient will be subjected to a lifetime of nutrition by vein and all the associated complications. This project is designed to understand the contribution of mucosal cell death to the process of intestinal regrowth. Understanding the exact molecular regulation of this important response may lead to innovative therapy intended to improve intestinal regrowth following a catastrophic loss of the intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059288-09
Application #
8080922
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Carrington, Jill L
Project Start
2001-04-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$373,364
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sun, Raphael C; Choi, Pamela M; Diaz-Miron, Jose L et al. (2017) Epithelial IGF1R is dispensable for IGF2 mediated enhanced intestinal adaptation in retinoblastoma-deficient mice. J Pediatr Surg 52:1026-1030
Warner, Brad W (2016) The Pathogenesis of Resection-Associated Intestinal Adaptation. Cell Mol Gastroenterol Hepatol 2:429-438
Choi, Pamela M; Sun, Raphael C; Guo, Jun et al. (2014) High-fat diet enhances villus growth during the adaptation response to massive proximal small bowel resection. J Gastrointest Surg 18:286-94; discussion 294
Rowland, Kathryn J; Diaz-Miron, Jose; Guo, Jun et al. (2014) CXCL5 is required for angiogenesis, but not structural adaptation after small bowel resection. J Pediatr Surg 49:976-80; discussion 980
Sun, Raphael C; Choi, Pamela M; Guo, Jun et al. (2014) Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection. J Pediatr Surg 49:966-70; discussion 970
Warner, Brad W (2013) Adaptation: paradigm for the gut and an academic career. J Pediatr Surg 48:20-6
Choi, Pamela; Guo, Jun; Erwin, Christopher R et al. (2013) IGF-2 mediates intestinal mucosal hyperplasia in retinoblastoma protein (Rb)-deficient mice. J Pediatr Surg 48:1340-7
Rowland, Kathryn J; Yao, Junjie; Wang, Lidai et al. (2013) Up-regulation of hypoxia-inducible factor 1 alpha and hemodynamic responses following massive small bowel resection. J Pediatr Surg 48:1330-9
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
Rowland, Kathryn J; McMellen, Mark E; Wakeman, Derek et al. (2012) Enterocyte expression of epidermal growth factor receptor is not required for intestinal adaptation in response to massive small bowel resection. J Pediatr Surg 47:1748-53

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