The role of IGF-II in scleroderma-associated pulmonary fibrosis

IGF-II 在硬皮病相关肺纤维化中的作用

• 批准号: 7763782
• 负责人: Eileen Hsu
• 金额: $ 2.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7763782
• 关键词: Autoimmune Diseases; Clinical; Collagen; Databases; Disease; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Goals; In Vitro; Insulin Receptor; Insulin-Like Growth Factor II; Lung; Mediating; Messenger RNA; Organ; Pathogenesis; Patients; Phenotype; Production; Proteins; Pulmonary Fibrosis; Recombinant Insulin-Like Growth Factor; Role; Scleroderma; Serum; Signal Transduction; Skin; Somatomedins; Structure of parenchyma of lung; System; Systemic Scleroderma; Twin Multiple Birth; cohort; in vivo; insight; mortality

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and multiple internal organs. SSc-related pulmonary fibrosis is the most common cause of SSc-related mortality, but currently no adequate therapies exist. The insulin-like growth factor (IGF) system has been implicated in the pathogenesis of pulmonary fibrosis. The role of IGF-II in the pathogenesis of fibrosis has been unexplored. We demonstrate that IGF-II expression is increased in vivo and in vitro in SSc lung tissue and primary lung fibroblasts. We also demonstrate that SSc lungs have increased IGF-II expression in fibroblastic foci. Furthermore, "IGF-II mRNA and protein levels are increased in primary lung fibroblasts from explanted lungs of patients with SSc, and recombinant-IGF-ll stimulates collagen and fibronectin production in primary lung fibroblasts. Our hypothesis is that IGF-II is abnormally expressed in SSc-related pulmonary fibrosis and contributes to disease pathogenesis by increasing extracellular matrix (ECM) production in fibroblasts. We propose to confirm our findings using lung tissues and primary fibroblasts and quantify levels of IGF-II secreted by SSc lung fibroblasts compared to normal lung fibroblasts. Additionally, we will compare systemic IGF-II levels in SSc patients of the Pittsburgh Scleroderma Database and Serum Bank and a cohort of twins discordant for SSc, and correlate IGF-II levels with pulmonary fibrosis and other clinical variables. We will examine the mechanism by which recombinant IGF-II mediates its effects. Specifically, we will determine whether the pro-fibrotic effects of IGF-II are mediated via the IGF-IR and/or Insulin Receptor (IR)-A in SSc and normal lung fibroblasts. We will also identify the signaling cascade activated by IGF-II in the induction of a fibrotic phenotype. Our goals are to characterize the aberrant expression of IGF-II in SSc-related pulmonary fibrosis and examine the mechanism(s) by which IGF-II increases ECM production and induces fibrosis. Our studies will allow further insight into the role of IGF-II in SSc-related pulmonary fibrosis.

描述（申请人提供）：系统性硬化症（SSc）是一种自身免疫性疾病，其特征是皮肤和多个内脏器官的纤维化。 SSc 相关的肺纤维化是 SSc 相关死亡的最常见原因，但目前尚无适当的治疗方法。胰岛素样生长因子（IGF）系统与肺纤维化的发病机制有关。 IGF-II 在纤维化发病机制中的作用尚未被探索。我们证明，在 SSc 肺组织和原代肺成纤维细胞中，IGF-II 表达在体内和体外均增加。我们还证明 SSc 肺在成纤维细胞灶中 IGF-II 表达增加。此外，“SSc 患者移植肺的原代肺成纤维细胞中的 IGF-II mRNA 和蛋白质水平增加，重组 IGF-II 刺激原代肺成纤维细胞中胶原蛋白和纤连蛋白的产生。我们的假设是 IGF-II 表达异常与 SSc 相关的肺纤维化有关，并通过增加成纤维细胞中细胞外基质 (ECM) 的产生来促进疾病的发病机制。我们建议使用肺组织和原代细胞来证实我们的发现。此外，我们将比较匹兹堡硬皮病数据库和血清库的 SSc 患者以及一组 SSc 不一致的双胞胎的全身 IGF-II 水平，并量化 SSc 肺成纤维细胞分泌的 IGF-II 水平。将 IGF-II 水平与肺纤维化和其他临床变量相关联 我们将研究重组 IGF-II 介导其作用的机制。 IGF-II 的促纤维化作用是否是通过 SSc 和正常肺成纤维细胞中的 IGF-IR 和/或胰岛素受体 (IR)-A 介导的。我们还将鉴定 IGF-II 在诱导纤维化表型中激活的信号级联。我们的目标是表征 SSc 相关肺纤维化中 IGF-II 的异常表达，并检查 IGF-II 增加 ECM 产生并诱导纤维化的机制。我们的研究将有助于进一步了解 IGF-II 在 SSc 相关肺纤维化中的作用。