REGULATION OF INTESTINAL EPITHELIAL GROWTH BY EGF FAMILY

表皮生长因子与转化的重要作用 生长因子-α在胃肠生理和免疫功能中的作用 在特定的疾病中，如溃疡病、梅内特里尔氏病和 胃肠道肿瘤继续被发现。EGF- 相关的多肽家族最近已经发展到包括至少5个 成员，包括双调节蛋白(AR)、肝素结合EGF样蛋白 生长因子(HB-EGF)和贝塔细胞蛋白(BTC)。初步数据 在此报告的以及由 另一些研究表明，在EGF家族中存在广泛的调控 会员。例如，每个EGF家族成员的表达为 通过对多种上皮细胞系的处理而诱导。在……里面 此外，同源基因在体内靶向干扰肿瘤生长因子α 重组导致TGFAlpha函数的替换， 可能是由相关的家庭成员所致，这样的表型 改动很小。这些观察结果强调了 EGF家族的整合性。这样做的总体目标是 提案的目的是增进人们对 EGF大家庭内的整合以及 肠上皮细胞增殖的整合 包括体内和体外技术。数据在支持中提交 AR和HB-EGF是即刻早期基因的模型 肠道上皮细胞及其诱导是一种 对净增殖性信号的重要贡献 表皮生长因子相关多肽。特定目标直接测试这一点 通过分析AR和HB的相对贡献来提出假说 表皮生长因子对肠上皮细胞系RIE-1增殖的影响 反义寡核苷酸和中和抗体的应用 具体目标#2和#3代表共同努力，将EGF- 比较相关多肽在体内的功能前景 它们在小肠和结肠中的分布分析 使用1)原位杂交和免疫组织化学，2) 病理生理操作，如禁食/再进食和 肠切除和3)转基因小鼠的功能研究 过量表达转化生长因子α和一个新的小鼠品系(EGFR/m1cwr) 靶向干扰表皮生长因子受体(EGFR)。这些研究 应该提高对正常细胞生长控制的理解 在选定的生理和病理生理情况下， 更全面地理解异常生长的先决条件 在肿瘤和其他肠道上皮细胞生长障碍中。

Important roles for epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) in gastrointestinal physiology and in specific diseases such as ulcer disease, Menetrier's disease and gastrointestinal neoplasia continue to be identified. The EGF- related peptide family recently has grown to include at least 5 members, including amphiregulin (AR), heparin-binding EGF-like growth factor (HB-EGF) and betacellulin (BTC). Preliminary data reported herein as well as in vivo and in vitro data published by others indicate that there is extensive regulation among EGF family members. For example, expression of each EGF family member is induced by treatment of a variety of epithelial cell lines. In addition, targeted disruption of TGFalpha in vivo by homologous recombination results in replacement of TGFalpha function, presumably by related family members, such that phenotypic alterations are minimal. These observations emphasize the integrated nature of the EGF family. The broad objective of this proposal is to advance understanding of the mechanisms of integration within the EGF family and also the implications of integration for intestinal epithelial cell proliferation by using both in vivo and in vitro techniques. Data is submitted in support of a model whereby AR and HB-EGF are immediate-early genes in intestinal epithelial cells and that their induction is an important contributor to the net proliferative signal induced by EGF-related peptides. Specific aim -1 directly tests this hypothesis by analysis of the relative contribution of AR and HB- EGF to intestinal epithelial cell (RIE-1 line) proliferation by the use of antisense oligonucleotides and neutralizing antibodies Specific aims #2 and #3 represent a concerted effort to place EGF- related peptides into functional perspective in vivo by comparative analysis of their distribution in the small intestine and colon using 1) in situ hybridization and immunohistochemistry, 2) pathophysiological manipulations such as fasting/refeeding and bowel resection and 3) functional studies of transgenic mice that over-express TGFalpha and a new mouse line (egfr/m1cwr) with targeted disruption of the EGF receptor (EGFr). These studies should improve understanding of growth control in normal cells and in selected physiological and pathophysiological circumstances, a prerequisite for a more complete understanding of aberrant growth in neoplasia and other disorders of intestinal epithelial growth.