Despite considerable recent interest, the mechanisms of intestinal adaptation following resection remain incompletely defined. While a variety of luminal and neuroendocrine stimuli probably play a role in this response, the hypothesis underlying this application is that the recently identified gut hormone glucagon-like peptide-2 (GLP-2) is a principal mediator and as such has considerable potential for clinical use in the treatment of disorders where mucosal growth is desireable, such as short bowel syndrome, parenteral nutrition-induced intestinal atrophy, and in the setting of intestinal injury. To begin to test this hypothesis, this application proposes a series of experiments designed to more fully characterize GLP-2, both in terms of its physiologic effects and its efficacy in several models of human disease. To this end, we plan to pursue the following specific aims: 1. To identify the cellular mechanisms of GLP-2's intestinotrophic effects. 2. To determine the other effects of GLP-2 on the gastrointestinal epithelium. 3. To examine the physiologic role and therapeutic potential of GLP-2 in intestinal adaptation and repair. The successful completion of these experiments should provide new insights into not only the actions of GLP-2, but also the mechanisms of intestinal growth and regeneration. We anticipate that the results of these studies will provide a basis for further clinical trials designed to test the therapeutic potential of GLP-2 in human disease.
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