Short bowel syndrome (SBS) often requires parenteral nutrition (PN). The long term objective is to understand the mechanisms by which enteral and parenteral nutrients stimulate the neuroendocrine system to produce functional adaptation to bowel resection.
Aims 1 & 2 will use well-characterized resection models that show differential mucosal growth in response to luminal nutrients and endogenous levels of GLP-2.
Aims 1 & 2 will test the hypothesis that the ability of luminal nutrients to stimulate intestinal adaptation is dependent on vagal afferent innervation and the intestinotrophic actions of glucagon-like peptide 2 (GLP-2) and insulin-like growth factor I (IGF-I). Studies will be performed in rats using a """"""""physiologic"""""""" resection model (Aim 1, 70% jejuno-ileal resection) and a """"""""clinical"""""""" resection model that mimics human SBS (Aim 2, 60% jejuno-ileal resection + cecectomy), and varying levels of enteral and parenteral nutrients. We will determine if the intestinotrophic response to GLP-2 infusion is reduced by functional ablation of vagal afferents in association with reduced GLP-2 and IGF-I responses. Activation of vagal neurons in the brainstem will be assessed by quantification of neurons expressing c-Fos. Intestinal adaptive growth will be assessed by changes in cellularity, structure and ion transport function. GLP-2 receptors will be localized in residual bowel by IHC using an antibody specific for the GLP-2 receptor. The relative abundance of proglucagon, GLP-2 receptor, IGF-I, IGF binding protein (IGFBP) -3 and -5 mRNAs will be determined by quantitative PCR or RNase protection assay, in some cases after laser capture microdissection.
Aim 3 will test the hypothesis that the final common pathway mediating resection-induced growth is IGF-I. We will establish primary cultures of subepithelial myofibroblasts from residual bowel of resected and transected rats to test in vitro how GLP-2 treatment affects expression of IGF-I and IGFBPs.
Aim 3 will also use knock out mice with deletion of IGFBP-3 and -5 to determine if mucosal hyperplasia induced by coinfusion of IGF-I and GLP-2 with PN solution is dependent on increased expression of IGFBP -3 and -5. Public Health: This proposal seeks to improve treatment for SBS by better understanding how food and growth factors promote recovery of the gut with the goal of reducing dependence on intravenous feeding. New therapies would reduce health care costs and improve well-being for approximately 30,000 Americans with SBS. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042835-16
Application #
7470076
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Maruvada, Padma
Project Start
1990-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2011-07-31
Support Year
16
Fiscal Year
2008
Total Cost
$241,602
Indirect Cost
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Sangild, Per T; Ney, Denise M; Sigalet, David L et al. (2014) Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges. Am J Physiol Gastrointest Liver Physiol 307:G1147-68
Murali, Sangita G; Brinkman, Adam S; Solverson, Patrick et al. (2012) Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice. Am J Physiol Gastrointest Liver Physiol 302:G794-804
Brinkman, Adam S; Murali, Sangita G; Hitt, Stacy et al. (2012) Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure. Am J Physiol Gastrointest Liver Physiol 303:G610-22
Baumler, Megan D; Koopmann, Matthew C; Thomas, Diana D H et al. (2010) Intravenous or luminal amino acids are insufficient to maintain pancreatic growth and digestive enzyme expression in the absence of intact dietary protein. Am J Physiol Gastrointest Liver Physiol 299:G338-47
Koopmann, Matthew C; Chen, Xueyan; Holst, Jens J et al. (2010) Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure. Am J Physiol Gastrointest Liver Physiol 299:G1222-30
Koopmann, Matthew C; Baumler, Megan D; Boehler, Christopher J et al. (2010) Total parenteral nutrition attenuates cerulein-induced pancreatitis in rats. Pancreas 39:377-84
Liu, Xiaowen; Murali, Sangita G; Holst, Jens J et al. (2009) Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats. Am J Physiol Regul Integr Comp Physiol 297:R1554-62
Koopmann, Matthew C; Liu, Xiaowen; Boehler, Christopher J et al. (2009) Colonic GLP-2 is not sufficient to promote jejunal adaptation in a PN-dependent rat model of human short bowel syndrome. JPEN J Parenter Enteral Nutr 33:629-38; discussion 638-9
Koopmann, Matthew C; Nelson, David W; Murali, Sangita G et al. (2008) Exogenous glucagon-like peptide-2 (GLP-2) augments GLP-2 receptor mRNA and maintains proglucagon mRNA levels in resected rats. JPEN J Parenter Enteral Nutr 32:254-65
Liu, Xiaowen; Murali, Sangita G; Holst, Jens J et al. (2008) Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats. Am J Physiol Regul Integr Comp Physiol 295:R1794-802

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