FIBROBLAST GROWTH FACTORS IN INFLAMMATORY BOWEL DISEASE

炎症性肠病中的成纤维细胞生长因子

• 批准号: 2518516
• 负责人: STEVEN M COHN
• 金额: $ 20.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518516
• 关键词: RNase protection assay; biological signal transduction; biopsy; cell differentiation; cellular pathology; colitis; cytokine; disease /disorder model; fibroblast growth factor; gastrointestinal epithelium; genetically modified animals; growth factor receptors; human subject; immunocytochemistry; in situ hybridization; inflammatory bowel diseases; integrins; intestinal mucosa; laboratory mouse; ligands; radiobiology; receptor expression; regeneration; tissue /cell culture; western blottings

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.

损伤后的粘膜再生包括正常的恢复 肠道功能和形态分化的区域模式和 是许多胃肠道疾病特有的病理特征。 包括炎症性肠病。成纤维细胞生长因子(FGFs) 是一组重要的调节分子，它们介导了许多 发生在胚胎发育过程中的形态发生过程 在伤口的发育和愈合过程中。这一点的中心假设是 建议是，成纤维细胞生长因子家族的成员在 IBD中上皮损伤修复的调控。这样做的长期目标是 该项目将使用体外、体内和转基因模型系统来 明确FGFs在调节上皮分化中的作用，细胞- IBD的再生和粘膜再生。《公约》的具体目标 建议：具体目标1)确定成纤维细胞生长因子受体的模式 和配体在IBD中的表达；特异性目的2)表征这些模式 成纤维细胞生长因子受体及其配体在IBD模型小鼠体内的表达 粘膜损伤-修复；特定目标3)确定FGFs对 肠上皮细胞功能和分化的测定 细胞因子对成纤维细胞生长因子及其受体表达的影响 培养中的肠上皮细胞。成纤维细胞生长因子受体及其配体的表达 将在炎症性疾病患者的正常组织样本中检测到 用核糖核酸酶对肠道疾病进行保护分析。细胞特有的模式 成纤维细胞生长因子受体的表达将通过免疫组织化学和 原位杂交。外源性成纤维细胞生长因子对细胞的影响 肠上皮细胞的分化将用CACO- 2细胞作为模型系统。成纤维细胞生长因子在整合素调控中的作用 我们将对表情进行检查。改变成纤维细胞生长因子介导的信号的作用 Caco-2细胞分化过程中的信号转导将用 转染正常成纤维细胞生长因子表达载体的细胞株 受体1序列或显性-负性突变形式的受体 能够抑制内源性成纤维细胞生长因子受体的信号转导。 炎性细胞因子对成纤维细胞生长因子受体表达的影响也将 在未分化和分化的Caco-2细胞中检测到Be。这个 FGFs及其受体在黏膜过程中的表达特征 利用辐射损伤模型和硫酸葡聚糖诱导的再生 结肠炎。