GROWTH FACTORS AND INFLAMMATORY BOWEL DISEASE

生长因子和炎症性肠病

• 批准号: 2147609
• 负责人: PAULINE K LUND
• 金额: $ 16.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2147609
• 关键词: Crohn's disease; binding proteins; cell cycle; cell growth regulation; cell type; cytokine; extracellular matrix; fibroblasts; fibrosis; gene expression; genetically modified animals; growth factor receptors; human subject; inflammatory bowel diseases; insulinlike growth factor; laboratory mouse; mesenchyme; smooth muscle; somatotropin; tissue /cell culture; ulcerative colitis

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD). Both diseases involve cycles of mucosal damage requiring mucosal restitution or regeneration to restore bowel function. In contrast to UC, CD is associated with transmural inflammation and fibrogenic complications, typified by submucosal granulomas altered mesenchymal cell proliferation and increased collagen deposition. Insulin- like growth factor I (IGF-I) expression is elevated in areas of fibrosis in bowel of animal models of chronic IBD. Expression of IGF-I and the related IGF-II is increased in involved bowel of patients with CD. IGFs prone proliferation of intestinal mesenchymal cells in vitro and intestinal epithelial cells in vitro and in vivo. Proposed studies will test the following hypotheses: 1. Phenotypically modified smooth muscle (SM) cells and/or fibroblasts (myofibroblasts) underlie fibrogenic complications of CD. 2. IGFs play an integral role in phenotypic modification or clonal expansion of the modified intestinal mesenchymal cells during development of fibrosis in CD. 3. Cytokines and/or extracellular matrix components within inflamed/fibrotic bowel of patients with CD induce IGF expression by intestinal mesenchymal cells or modulate IGF responsiveness by effects on IGF receptors or IGF binding proteins (IGFBPs). To test these hypotheses: Aim 1 will elucidate the precise mesenchymal cell types that express IGF-I and IGF-II and show increased collagen deposition in inflamed or fibrotic regions of bowel from patients with CD. Aim 2 will analyze cultured human intestinal smooth muscle cells and fibroblasts/myofibroblasts: a) to test IGF effects on proliferation, collagen deposition and phenotype in normal cells, b) to test effects of cytokines or extracellular matrix from inflamed/fibrotic bowel on IGF expression, phenotype and IGF responsiveness of normal cells and c) to examine whether cells from patients with CD show altered IGF expression or responsiveness compared with cells from patients with UC or noninflammatory bowel disease. Aim 3 will use GH, IGF-I and IGFBP 1 transgenic mice (mice with inducible overexpression of IGFBP 1 a natural inhibitor of IGF-l action) to define in vivo effects of altered IGF-I production or action on susceptibility, course, severity and histopathology of experimental bowel inflammation and fibrosis.

克罗恩病（CD）和溃疡性结肠炎（UC）是慢性炎症性疾病， 肠道疾病（IBD）。这两种疾病都涉及粘膜损伤的循环 需要粘膜恢复或再生以恢复肠功能。 与UC相反，CD与透壁性炎症相关， 纤维化并发症，以改变的粘膜下肉芽肿为代表 间充质细胞增殖和增加的胶原沉积。胰岛素- 类生长因子I（IGF-I）表达在纤维化区域升高 在慢性IBD动物模型肠道中。IGF-I的表达与胰岛素抵抗 相关的IGF-II在CD患者的受累肠中增加。IGFs 肠间充质细胞在体外和肠 体外和体内的上皮细胞。 拟议的研究将测试 以下假设：1.表型修饰的平滑肌（SM）细胞 和/或成纤维细胞（肌成纤维细胞）是纤维化并发症的基础。 CD. 2. IGFs在表型修饰或克隆形成中起着不可或缺的作用。 发育过程中修饰的肠间充质细胞的扩增 CD的纤维化 3.细胞因子和/或细胞外基质成分 在CD患者的发炎/纤维化肠内诱导IGF表达 或调节IGF反应性的影响 对胰岛素样生长因子受体或胰岛素样生长因子结合蛋白（IGFBPs）的作用。测试这些 假设：目的1将阐明确切的间充质细胞类型， 表达IGF-I和IGF-II，并在炎症组织中显示胶原沉积增加。 或来自CD患者的肠纤维化区域。目标2将分析 培养的人肠平滑肌细胞， 成纤维细胞/肌成纤维细胞：a）测试IGF对增殖的作用， 正常细胞中的胶原沉积和表型，B）测试 炎症/纤维化肠细胞因子或细胞外基质对IGF的影响 正常细胞的表达、表型和IGF反应性，和 检查CD患者的细胞是否显示IGF表达改变， 与来自UC或非炎症患者的细胞相比， 肠道疾病。 目的3：利用GH、IGF-I和IGFBP 1转基因小鼠（小鼠 IGFBP 1（一种IGF-I的天然抑制剂）的诱导性过表达 作用），以确定改变的IGF-I产生或作用于 实验性肠道疾病易感性、病程、严重程度和组织病理学 炎症和纤维化。