INTESTINAL ADAPTATION AND EPIDERMAL GROWTH FACTOR

肠道适应和表皮生长因子

• 批准号: 6342502
• 负责人: BRAD Wayne WARNER
• 金额: $ 14.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342502
• 关键词: apoptosis; biological signal transduction; cell differentiation; cell migration; cell proliferation; epidermal growth factor; gastrointestinal absorption /transport; genetically modified animals; growth factor receptors; ileum; immunocytochemistry; immunoprecipitation; in situ hybridization; intestine surgery; laboratory mouse; messenger RNA; monoclonal antibody; northern blottings; protease inhibitor; protein tyrosine kinase; receptor binding; receptor expression; small intestines; tissue /cell culture; western blottings

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.

大量肠道长度的丧失会导致大量的 发病率和死亡率，并与多种疾病有关 包括克隆氏病、S病、创伤、肠扭转和坏死性肠炎 小肠结肠炎。适应是对剩余的一个重要反应 肠道肥大、增生和消化增加 和吸收能力。表皮生长因子(EGF)已被发现 通过一种未知的机制增强这种反应(S)。这项建议 将检验适应是由EGF及其受体介导的假设 肠细胞受体(EGF-R)我们已经为MASSIC(50)开发了一个模型 百分比)在小鼠的小肠切除术(SBR)中启用直接 EGF/EGF-R基因操作对人类免疫功能影响的研究 适应。肠上皮细胞生长因子受体基因和蛋白表达的变化 SBR之后的活动将被确定。适应将是 在以下SBR操作模型的背景下进行了分析 EGF/EGF-R轴。EGF/EGF-R轴将受到以下刺激 给予EGF，靶向肠道EGF过表达和 转基因小鼠和过表达TGFα的转基因小鼠中的EGF-R (EGF-R的另一个配体)。EGF/EGF-R轴抑制模型的建立 将包括手术切除EGF产生的主要来源 小鼠(颌下腺)注射EGF-R蛋白 酪氨酸激酶抑制剂和一种存在缺陷的小鼠 EGF-R信号转导的研究进展。我们将检验这一假设 EGF/EGF-R轴刺激增强适应的机制是通过 增加肠细胞增殖率和降低增殖率 程序性细胞死亡(细胞凋亡)。肠道细胞迁移， 分化、增殖和凋亡将被确定 在SBR之后，然后在EGF/EGF-R模型的背景下进行研究 轴操作。对EGF/EGF-R轴的进一步了解是 对开发设计的新治疗策略至关重要 增强肠道对大量肠道丢失的适应性反应。