GROWTH FACTORS AND INFLAMMATORY BOWEL DISEASE

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)。这两种疾病都涉及黏膜损伤的循环。 需要粘膜修复或再生来恢复肠道功能。 与UC不同的是，CD与跨壁炎症和 纤维性并发症，以粘膜下肉芽肿改变为典型 间充质细胞增殖，胶原沉积增多。胰岛素- 类生长因子I(IGF-I)在纤维化区的表达升高 在慢性IBD动物模型的肠道内。胰岛素样生长因子-I及其受体的表达 CD患者病变肠段相关IGF-II水平升高。IGFS 肠间充质细胞在体外和肠道易增殖的研究 体外和体内培养上皮细胞。拟议的研究将测试 以下假设：1.表型修饰的平滑肌细胞 和/或成纤维细胞(肌成纤维细胞)是导致纤维性并发症的基础 CD.2.IGFS在表型修饰或克隆中起着不可或缺的作用 修饰后的肠道间充质细胞在发育过程中的扩增 CD中的纤维化症。3.细胞因子和/或细胞外基质成分 CD患者炎性/纤维化肠腔内IGF诱导表达 通过肠道间充质细胞或通过效应调节IGF反应性 胰岛素样生长因子受体或胰岛素样生长因子结合蛋白(IGFBPs)。为了测试这些 假设：目标1将阐明准确的间充质细胞类型 炎症时IGF-I和IGF-II的表达及胶原沉积的增加 或CD患者的肠纤维化区。AIM 2将分析 培养的人肠平滑肌细胞和 成纤维细胞/肌成纤维细胞：a)为了测试IGF对增殖的影响， 在正常细胞中的胶原沉积和表型，b)测试 炎症/纤维化肠壁细胞因子或细胞外基质对胰岛素样生长因子的影响 正常细胞和c)的表达、表型和IGF反应性 检查CD患者的细胞是否显示IGF表达改变或 与UC或非炎症性疾病患者细胞的反应性比较 肠病。AIM 3将使用GH、IGF-I和IGFBP 1转基因小鼠(小鼠 胰岛素样生长因子-L天然抑制物IGFBP1的诱导过表达 行动)以确定改变的IGF-I的产生或作用在体内的影响 实验性肠道的易感性、病程、严重程度和组织病理学 炎症和纤维化。

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.