Growth Factors and Inflammatory Bowel Disease

描述(申请人提供)：这项研究的主要目标是更好地了解炎症诱导的肠纤维化的积极和消极介质，这是克罗恩病(CD)的一种不可治愈的并发症。在急性结肠炎动物模型和CD患者中的研究结果表明，生长激素(GH)治疗CD有好处，但GH和由GH诱导的胰岛素样生长因子-I(IGF-I)的纤维化作用已被证实，支持GH治疗可能加剧CD纤维化的假说。在CD和慢性肠炎动物模型中，局部表达的IGF-I在纤维化部位的肌成纤维细胞中上调，这表明IGF-I是纤维化的内源性介质。初步数据支持一种假说，即细胞因子信号转导抑制物(SOCs)可能限制治疗性或内源性细胞因子和生长因子在炎症肠道中的纤维化作用。其他数据支持一种假设，即IGF-I与另一种关键细胞因子--肿瘤坏死因子-α相互作用，以调节肠肌成纤维细胞的胶原合成或增殖，而成纤维细胞是CD纤维化的关键细胞介质。具体目标如下：目标1将确定在PG-PS诱导的小肠结肠炎期间，全身性GH是否增加纤维化、循环或局部表达的IGF-I。将评估SOCS2或SOCS3的细胞位置和水平，以验证SOCS2或SOCS3在体内表达，从而允许它们限制纤维化。AIM 2将确定IGF-I是否介导GH对肠肌成纤维细胞胶原合成或增殖的作用，并测试SOCS是否限制GH或IGF-I的作用。AIM 3将定义SOCS2绝对或间质特异性缺乏的小鼠在TNBS结肠炎期间是否表现出改变的纤维化、JGF-I诱导或GH作用。AIM 4将确定TNF-α与IGF-I是否具有相加或协同作用，以诱导肠道肌成纤维细胞胶原合成，以及SOCS是否限制这些作用。

DESCRIPTION (provided by applicant): Major objectives of this research are to gain a better understanding of positive and negative mediators of inflammation induced intestinal fibrosis, an incurable complication of Crohn's disease (CD). Findings in animal models of acute colitis and in patients with CD indicate benefits of growth hormone (GH) therapy in CD but the documented fibrogenic effects of GH and insulin-like growth factor-I (IGF-I) which is induced by GH, support a hypothesis that GH therapy may exacerbate fibrosis in CD. Locally expressed IGF-I is up-regulated in myofibroblasts at sites fibrosis in CD and animal models of chronic intestinal inflammation implicating IGF-I as an endogenous mediator of fibrosis. Preliminary data support a hypothesis that suppressors of cytokine signaling (SOCS), may limit the fibrogenic actions of therapeutic or endogenous cytokines and growth factors in the inflamed intestine. Other data support a hypothesis that IGF-I interacts with another key cytokine, TNF-alpha to mediate collagen synthesis or proliferation in intestinal myofibroblasts, key cellular mediators of fibrosis in CD. Specific aims are as follows:Aim 1 will define if systemic GH increases fibrosis, circulating or locally expressed IGF-I during PG-PS induced enterocolitis. Cellular sites and levels of SOCS expression will be assessed to verify that SOCS2 or SOCS3 are expressed at in vivo sites that would permit them to limit fibrosis.Aim 2 will define if IGF-I mediates GH action on collagen synthesis or proliferation in intestinal myofibroblasts and test whether SOCS limit GH or IGF-I action.Aim 3 will define if mice with absolute or mesenchyme-specific SOCS2 deficiency show altered fibrosis, JGF-I induction or GH action during TNBS-colitis.Aim 4 will define mechanisms if TNF-alpha has additive or synergistic effects with IGF-I, to induce collagen synthesis in intestinal myofibroblasts and if SOCS limit these effects.