Growth Factors and Inflammatory Bowel Disease

描述（由申请人提供）：本研究的主要目的是更好地了解炎症性肠纤维化的阳性和阴性介质，肠纤维化是克罗恩病（CD）的一种无法治愈的并发症。急性结肠炎动物模型和乳糜泻患者的研究结果表明，生长激素（GH）治疗对乳糜泻患者有益，但GH和胰岛素样生长因子- i （IGF-I）的纤维化作用已被证实，这支持了GH治疗可能加剧乳糜泻纤维化的假设。在乳糜泻纤维化部位的肌成纤维细胞中，IGF-I的局部表达上调，慢性肠道炎症动物模型表明IGF-I是一种内源性纤维化介质。初步数据支持一种假设，即细胞因子信号的抑制因子（SOCS）可能限制炎症肠道中治疗性或内源性细胞因子和生长因子的纤维化作用。其他数据支持IGF-I与另一个关键细胞因子tnf - α相互作用，介导肠肌成纤维细胞胶原合成或增殖，肠肌成纤维细胞是CD中纤维化的关键细胞介质。具体目的如下：Aim 1将确定PG-PS诱导小肠结肠炎期间，全身性GH是否增加纤维化、循环或局部表达的IGF-I。将评估soccs表达的细胞位点和水平，以验证SOCS2或SOCS3是否在允许它们限制纤维化的体内位点表达。目的2将确定IGF-I是否介导生长激素对肠肌成纤维细胞胶原合成或增殖的作用，并测试SOCS是否限制生长激素或IGF-I的作用。目的3将确定具有绝对或间质特异性SOCS2缺陷的小鼠在tnbs -结肠炎期间是否表现出纤维化改变、jgf - 1诱导或GH作用。目的4将确定tnf - α是否与IGF-I具有附加或协同作用，诱导肠肌成纤维细胞中的胶原合成，以及SOCS是否限制这些作用的机制。

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.