FIBROBLAST GROWTH FACTORS IN INFLAMMATORY BOWEL DISEASE

损伤后的粘膜再生包括恢复正常的 肠道功能和形态分化的区域模式， 是许多胃肠道疾病的典型病理特征 包括炎症性肠病成纤维细胞生长因子（FGF） 是一组重要的调节分子， 形态发生过程发生在胚胎发生期间，在胎儿 发展，以及伤口愈合。这个问题的核心假设是 建议是，FGF家族成员在 IBD中上皮损伤修复的调节。这一长期目标 该项目将使用体外，体内和转基因模型系统， 定义FGF在调节上皮分化、细胞分化和细胞增殖中的作用。 更新和粘膜再生。的具体目标 具体目的：1）确定FGF受体的模式 和IBD中的配体表达;具体目的2）表征模式 在IBD的体内小鼠模型中FGF受体和配体的表达， 3）确定FGF对粘膜损伤修复的作用， 肠上皮细胞功能和分化，并确定 细胞因子对成纤维细胞生长因子及其受体表达的影响 培养的肠上皮细胞。FGF受体和配体表达 将在来自患有炎性疾病的患者的正常组织样品中测定 肠道疾病使用RNase保护分析。细胞特异性模式 FGF受体表达将通过免疫组织化学和免疫组织化学方法测定。 原位杂交外源性FGF对细胞增殖的影响 肠上皮细胞的分化将使用Caco- 2细胞作为模型系统。FGF在调节整合素中的作用 表达将被检查。改变FGF介导的信号的影响 Caco-2细胞分化过程中的转导将使用 用表达正常FGF的质粒转染的细胞系 受体1序列或该受体的显性失活突变体形式， 能够抑制内源性FGF受体的信号转导。 炎症细胞因子对FGF受体表达的影响也将 B e在未分化和分化的Caco-2细胞中测定。的 FGF及其受体的表达将在粘膜过程中表征。 再生使用辐射损伤模型和硫酸葡聚糖诱导的 结肠炎

Mucosal regeneration following injury involves restoration of normal regional patterns of functional and morphological gut differentiation and is a characteristic pathological feature of many gastrointestinal diseases including inflammatory bowel disease. The fibroblast growth factors (FGFs) are an important group of regulatory molecules that mediate a number of morphogenic processes occurring during embryogenesis, during fetal development, and during wound-healing. The central hypothesis of this proposal is that members of the FGF family play a pivotal role in the regulation of epithelial injury-repair in IBD. The long term goals of this project will be to use in vitro, in vivo, and transgenic model systems to define the roles of FGFs in regulating epithelial differentiation, cell- renewal, and mucosal regeneration in IBD. The specific aims of the proposal are: specific aim 1) To determine the patterns of FGF receptor and ligand expression in IBD; specific aim 2) To characterize the patterns of FGF receptor and ligand expression in in vivo mouse models of IBD and mucosal injury-repair; specific aim 3) To determine the effects of FGFs on intestinal epithelial cell function and differentiation and to determine the effects of cytokines on expression of FGFs and FGF receptors in intestinal epithelial cells in culture. FGF receptor and ligand expression will be determined in normal tissue samples from patients with inflammatory bowel disease using RNase protection analysis. Cell-specific patterns of FGF receptor expression will be determined by immunohistochemistry and in situ hybridization. The effects of exogenous FGFs on cellular differentiation of intestinal epithelial cells will be examined using Caco- 2 cells as a model system. The role of FGFs in regulating integrin expression will be examined. The effects of altering FGF mediated signal transduction during differentiation of Caco-2 cells will be analyzed using cell lines transfected with plasmids expressing either the normal FGF receptor 1 sequence or a dominant-negative mutant form of the receptor that is capable of inhibiting signal transduction by endogenous FGF receptors. The effects of inflammatory cytokines on FGF receptor expression will also b e determined in undifferentiated and differentiated Caco-2 cells. The expression of FGFs and their receptors will be characterized during mucosal regeneration using a radiation-injury model and in dextran sulfate induced colitis.