Short bowel syndrome often requires permanent total parenteral nutrition. Current treatment is inadequate because TPN induces serious complications and is expensive. A greater understanding of the mechanisms underlying intestinal adaptation to resection is needed to develop improved treatments. The focus of this research is to characterize the local and humoral signals that mediate intestinal adaptation to resection during TPN. The long term goal is to understand the mechanisms by which parenteral nutrients and growth factors, such as insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2), regulate intestinal adaptation to design TPN protocols that will optimize intestinal function and permit transition to enteral feeding. There are three specific aims.
Specific aim 1 determines if the stimulation of mucosal hyperplasia induced by IGF-I is modulated by expression of IGF binding protein-5 (IGFBP-5) by conducting TPN studies in IGFBP-5 transgenic knock-out mice treated with rhIGF-I.
Specific aim 2 determines how resection and administration of rhIGF-I and rhGLP-2 mediate adaptation of the jejunum and colon in a resection model which mimics human short bowel syndrome as adaptation does not occur and TPN is required. TPN rats will be subjected to intestinal resection (60 percent jejuno-ileal resection plus cecectomy), treated with growth factors, and weaned to enteral feeding. Adaptation will be assessed by changes in intestinal structure (morphology, composition, proliferation, migration and apoptosis) and function (ion transport using Ussing flux chambers, enzymes and ability to transition to enteral feeding).
Specific aim 3 will determine how the physiological significance of endogenous GLP-2 in resection induced mucosal growth in rats given 70 percent jejuno-ileal resection and maintained with TPN. When there is residual ileum present, plasma bioactive GLP-2 is increased and dramatic resection-induced jejunal hyperplasia occurs with TPN. The hypothesis is that resection and parenteral lipids stimulate GLP-2 secretion, which partially mediates intestinal growth by interaction with GLP-2 receptors. The PI proposes to determine if parenteral lipid and pancreaticobiliary secretions increase ileal proglucagon mRNA and plasma GLP-2 and if the mucosal hyperplasia induced by resection is associated with an increase in jejunal GLP-2 receptor number or affinity.
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