INTESTINAL ADAPTATION AND EPIDERMAL GROWTH FACTOR

显著的肠长度的损失导致大量的 发病率和死亡率，并与多种疾病相关 包括克罗恩病、创伤、肠扭转和坏死性 肠炎 适应是其余国家的一个重要对策。 肠道由肥大、增生和消化道增加组成 吸收能力。 表皮生长因子（EGF） 以通过未知的机制增强这种响应。 这项建议 将测试的假设，适应是介导的EGF及其 肠上皮细胞受体（EGF-R）。 我们已经开发了一个模型，大规模（50 %）的小鼠小肠切除术（SBR），以实现直接肠切除。 研究EGF/EGF-R基因操作的后果， 适应 肠EGF-R mRNA和蛋白表达的变化 并测定SBR后的活性。 适应将是 分析了以下SBR的背景下，模型的操纵 EGF/EGF-R轴 EGF/EGF-R轴将被激活， 表皮生长因子（EGF），表皮生长因子（EGF）的靶向肠道过表达， 转基因小鼠和过表达TGF α的转基因小鼠中的EGF-R （EGF-R的另一种配体）。 EGF/EGF-R轴抑制模型 将包括手术切除EGF生产的主要来源， 小鼠（下颌下腺），给予EGF-R蛋白 酪氨酸激酶抑制剂和一种具有缺陷的小鼠品系 EGF-R信号转导。 我们将测试假设， 通过EGF/EGF-R轴刺激增强适应的机制是 增加肠上皮细胞增殖的速率以及降低 程序性细胞死亡（apoptosis）肠细胞迁移， 分化、增殖和凋亡将被确定， 随后SBR，然后在EGF/EGF-R模型的背景下研究 轴操纵 EGF/EGF-R轴的研究进展 对于开发新的治疗策略至关重要， 以增强肠道对大量肠道损失的适应性反应。

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.