INTESTINAL ADAPTATION AND EPIDERMAL GROWTH FACTOR

点击翻译按钮获取中文摘要

The loss of significant intestinal length results in substantial morbidity and mortality and is associated with multiple conditions including Crohn s disease, trauma, intestinal volvulus, and necrotizing enterocolitis. Adaptation is an important response of the remaining bowel consisting of hypertrophy, hyperplasia, and increased digestive and absorptive capacity. Epidermal growth factor (EGF) has been shown to enhance this response by an unknown mechanism(s). This proposal will test the hypothesis that adaptation is mediated by EGF and its enterocyte receptor (EGF-R). We have developed a model for massive (50 percent) small bowel resection (SBR) in the mouse to enable a direct study of the consequences of EGF/EGF-R gene manipulation during adaptation. Changes in intestinal EGF-R mRNA and protein expression and activity following SBR will be determined. Adaptation will be analyzed following SBR in the context of models for manipulation of the EGF/EGF-R axis. The EGF/EGF-R axis will be stimulated by administration of EGF, targeted intestinal overexpression of EGF and EGF-R in transgenic mice, and transgenic mice that overexpress TGFalpha (another ligand for the EGF-R). Models for EGF/EGF-R axis inhibition will include surgical removal of the major source of EGF production in the mouse (submandibular glands), administration of EGF-R protein tyrosine kinase inhibitors, and a strain of mouse harboring a defect of EGF-R signal transduction. We will test the hypothesis that the mechanism for enhanced adaptation by EGF/EGF-R axis stimulation is by increasing rates of enterocyte proliferation as well as reducing rates of programmed cell death (apoptosis). Enterocyte migration, differentiation, proliferation, and apoptosis will be determined following SBR and then studied in the context of models for EGF/EGF-R axis manipulation. Further understanding of the EGF/EGF-R axis is crucial toward the development of novel therapeutic strategies designed to enhance the intestinal adaptive response to massive intestinal loss.