grantor:
University of TorontoIn the following set of studies, we demonstrate for the first time that exogenous administration of a human degradation resistant analog, h[Gly2]-GLP-2, attenuated intestinal damage in rodent models of small and large intestinal injury, and following the administration of chemotherapy in both non-tumour and tumour bearing mice. Several novel concepts have emerged from these experiments regarding the biology of GLP-2 'in-vivo': (i) In the experimental models that examined the effect of different GLP-2 treatment regimens on animal survival and intestinal growth parameters, the administration of GLP-2 as a pretreatment regimen was more effective then administration of GLP-2 concomitantly with or following the onset of intestinal injury. (ii) In addition to enhancing cellular proliferation within the small and large intestinal crypts, GLP-2 inhibited apoptotic cell death in a position-dependent manner within the crypt cell compartment and in heterologous cells expressing the GLP-2 receptor (BHK-GLP-2R cells). (iii) GLP-2 treatment attenuated the systemic dissemination of intestinal bacterial flora commonly observed following intestinal epithelial injury. (iv) GLP-2 treatment reduced intestinal proinflammatory TH1 and macrophage-derived cytokine levels, reduced neutrophil infiltration following the onset of intestinal inflammation, and attenuated chemotherapy and indomethacin-induced leukopenia. (v) Circulating levels of the GLP-2 degrading enzyme dipeptidyl peptidase IV (DPP-IV) were reduced in human patients with both Crohn's disease and ulcerative colitis. Changes in circulating DPP-IV activity, resulting in increased levels of biologically active GLP-2, emphasize the importance of endogenous GLP-2 clearance as part of the normal intestinal adaptive response to injury. Taken together, the experimental studies presented in this thesis have contributed novel insights into the actions of GLP-2 at the molecular, cellular, and whole organism level in the setting of intestinal disease. While many unanswered questions remain, the present set of studies raise the possibility of utilizing GLP-2 in the treatment of several human conditions, including inflammatory bowel diseases and chemotherapy-induced enteritis, and provide a scientific rationale for future human experimentation.Ph.D
