REGULATION OF INSULIN LIKE GROWTH FACTOR I

描述 （改编自申请人摘要）间质性肺病是 包括大量的异质性肺部疾病， 共同的是，炎症的初始阶段之后是旺盛的阶段， 纤维化 无情的纤维化被无情的 呼吸功能不全 作为一个群体，治疗这些患者 疾病在很大程度上令人失望。 肺泡巨噬细胞发挥着 通过分泌生长因子在特发性肺纤维化中发挥重要作用， 是成纤维细胞增殖和活化所必需的。 的许多 巨噬细胞表达的生长因子，胰岛素样生长因子-I （IGF-1）已被强烈联系到发病机制和进展， 肺纤维化通过刺激成纤维细胞增殖， 合成胶原蛋白。 该实验室以前的工作表明， IGF-1的表达被TNF α增强并被显著抑制 IFN γ在转录水平对小鼠巨噬细胞的影响。 整体 这一建议的目的是确定这两个机制， 关键过程发生。 基于先前的发现，已知TNF α 激活促分裂原活化蛋白激酶/细胞外信号 MAPK/ERK和c-Jun激酶/应激活化蛋白激酶 (JNK/SAPK）信号转导途径（其可以激活c-Fos和c-Jun， 并且IGF-I启动子含有识别位点 AP-I转录因子（由c-Jun的同源二聚体或 c-Jun-c-Fos的异源二聚体），我们建议测试假设， 对TNF α的反应中IGF-I的表达增加是由 MAPK/ERK和JNK/SAPK通路的联合激活， IGF-I基因的转录通过AP-1转录的形成 因子 根据先前的报道，IGF-I的下调 IFNY的表达不是由于IGF-I mRNA的不稳定性，而是一个过程， 需要活跃的蛋白质合成，我们建议测试假设 IFNY通过诱导和/或激活抑制因子来沉默IGF-I表达， 蛋白质，即反式作用因子，结合于 IGF-I基因，顺式作用元件。 基于第一个假设， 转录增强子复合物AP-1在IGF-1合成中是关键的， 我们将检验AP-1的组分c-jun和c-Fos将 在肺结核患者的肺中， 纤维化

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.