REGULATION OF INSULIN LIKE GROWTH FACTOR I

描述 (改编自申请人的摘要)间质性肺病 由大量的异质性肺部疾病组成， 常见的是，最初的炎症阶段之后是旺盛的阶段 纤维化症。不可阻挡的纤维化伴随着无情的病程 呼吸功能不全。作为一个群体，治疗这些患者 失调症在很大程度上令人失望。肺泡巨噬细胞发挥重要作用 分泌生长因子在特发性肺纤维化中的重要作用 是成纤维细胞增殖和激活所必需的。在众多人中 巨噬细胞表达的生长因子、胰岛素样生长因子-I 胰岛素样生长因子-1(IGF-1)与骨肉瘤的发病和发展密切相关。 刺激成纤维细胞增殖并促进肺纤维化 合成胶原蛋白。这个实验室之前的工作表明， 肿瘤坏死因子α促进胰岛素样生长因子-I的表达并显著抑制其表达 在小鼠巨噬细胞中通过转录水平的IFNGamma。整体而言 这项提案的目标是确定这两个 关键过程会发生。基于先前的发现，即已知肿瘤坏死因子α 激活丝裂原激活的蛋白激酶/细胞外信号 调节蛋白激酶(MAPK/ERK)与c-jun蛋白/应激激活蛋白激酶 (JNK/SAPK)信号转导通路(可以激活c-Fos和c-Jun， 分别)，并且IGF-I启动子包含一个识别位点 AP-I转录因子(由c-jun的同源二聚体或a C-jun-c-Fos的异源二聚体)，我们建议检验这一假设 肿瘤坏死因子α诱导的胰岛素样生长因子-I表达增加是由 MAPK/ERK和JNK/SAPK信号通路的联合激活 通过形成AP-1转录实现IGF-I基因的转录 因素。基于之前的报道，IGF-I的下调 IFNY的表达不是由于IGF-I mRNA的不稳定，而是一个过程 这需要活跃的蛋白质合成，我们建议检验这一假说 干扰素通过诱导和/或激活抑制物抑制IGF-I的表达 蛋白(S)，反式作用因子，结合在5‘-侧翼区域 IGF-I基因，顺式作用元件。基于第一个假设 转录增强子复合体AP-I在IGF-I的合成中起关键作用， 我们将检验AP-1的成分c-jun和c-Fos将 在肺癌患者的肺组织中发现丰度增加 纤维化症。

DESCRIPTION (Adapted from the applicant's abstract) The interstitial lung diseases are comprised of a large collection of heterogenous pulmonary disorders having in common an initial phase of inflammation followed by a phase of exuberant fibrosis. The inexorable fibrosis is paralleled by a course of relentless respiratory insufficiency. As a group, treatment of patients with these disorders have been largely disappointing. Alveolar macrophages play a vital role in idiopathic pulmonary fibrosis by secreting growth factors that are essential for fibroblast proliferation and activation. Of the many growth factors expressed by macrophages, insulin-like growth factor-I (IGF-1) has been strongly linked to the pathogenesis and progression of pulmonary fibrosis by stimulating fibroblasts to proliferate and to synthesize collagen. Previous work from this laboratory has shown that the expression of IGF-I is augmented by TNFalpha and is dramatically inhibited by IFNgamma at the transcriptional level in murine macrophages. The overall goal of this proposal is to determine the mechanism by which these two critical processes occur. Based on previous findings that TNFalpha is known to activate both the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) and c-Jun kinase/stress-activated protein kinase (JNK/SAPK) signal transduction pathways (which can activate c-Fos and c-Jun, respectively) and that the IGF-I promoter contains a recognition site for the AP- I transcription factor (composed of either a homodimer of c-Jun or a heterodimer of c-Jun-c-Fos), we propose to test the hypothesis that the increased expression of IGF-I in response to TNFalpha is mediated by the joint activation of the MAPK/ERK and JNK/SAPK pathways which then enhance transcription of the IGF-I gene by the formation of the AP-1 transcription factor. Based on previous reports that the down-regulation of IGF-I expression by IFNY is not due to IGF-I MRNA instability but rather a process that requires active protein synthesis, we propose to test the hypothesis that IFNY silences IGF-I expression by inducing and/or activating repressor protein(s), the trans acting factor, that binds to the 5'-flanking region of the IGF-I gene, the cis-acting element. Based on the first hypothesis that the transcriptional enhancer complex AP- I is critical in IGF-I synthesis, we will test the hypothesis that components of AP-1, c-jun and c-Fos, will be found in increased abundance in the lungs of patients with pulmonary fibrosis.