Role of Fibroblast Thy-1 in Pulmonary Fibrosis

成纤维细胞 Thy-1 在肺纤维化中的作用

• 批准号: 6613065
• 负责人: James S. Hagood
• 金额: $ 0.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-22 至 2006-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613065
• 关键词: biological signal transduction; biomarker; bone marrow transplantation; cell growth regulation; cell proliferation; fibroblasts; fibrogenesis; gene targeting; glycoproteins; glycosylphosphatidylinositols; growth factor; human tissue; idiopathic pulmonary fibrosis; interleukin 1; laboratory mouse; pulmonary fibrosis /granuloma; tissue /cell culture

Fibrotic scarring of the lung causes significant disability, often leading to death. Persistent fibroblast proliferation is resistant to treatment and portends a poor prognosis. The expression of Thy-1 glycoprotein seems to be a key element affecting the fibrotic potential of fibroblasts. Fibroblasts lacking Thy-1 (Thy-1-) share many of the phenotypic features characteristic of fibroblasts from fibrotic lesions and have enhanced proliferative responses to fibrogenic growth factors, which may lead to their accumulation or persistence in fibrotic lesions. The proposed studies are based on the hypothesis that the expression of Thy-1 alters activation of intracellular signaling pathways and cellular responses to fibrogenic mediators, thus modulating the fibroproliferative potential of fibroblasts. The mechanisms for differential signaling and the implications for fibrosis will be explored through the following specific aims: 1) To elucidate the molecular mechanisms for the enhanced proliferative responses observed in Thy-1- fibroblasts, by defining intracellular signaling pathways modulating proliferative responses and by defining the effects of Thy-1 expression on signaling and proliferation; 2) To characterize the consequences of Thy-1 expression in experimentally-induced lung fibrosis, by comparing fibrosis in Thy-1-/- gene-targeted mice to those in wild-type mice, and in chimeric Thy-1-/- mice in which hematopoietic cell expression of Thy-1 has been restored by bone marrow transplantation; and 3) To determine the role of fibroblast Thy-1 expression in idiopathic pulmonary fibrosis, by exploring fibroblast proliferation and signaling in situ and ex vivo in explanted lungs from IPF patients undergoing lung transplantation, compared to those in control tissues. Understanding the roles of subpopulations of fibroblasts in lung fibrogenesis, and the mechanisms of their activation, is likely to provide rationale for novel cell- and pathway-specific therapeutic interventions for this debilitating process.

肺的纤维化瘢痕形成导致严重残疾，通常导致死亡。 持续的成纤维细胞增殖对治疗有抗性，预示着预后不良。 Thy-1糖蛋白的表达似乎是影响成纤维细胞纤维化潜能的关键因素。缺乏Thy-1（Thy-1-）的成纤维细胞具有纤维化病变成纤维细胞的许多表型特征，并对纤维化生长因子具有增强的增殖反应，这可能导致其在纤维化病变中的积累或持续存在。 提出的研究是基于这样的假设，即Thy-1的表达改变了细胞内信号传导途径的激活和细胞对纤维化介质的反应，从而调节成纤维细胞的纤维增殖潜力。 1）阐明Thy-1-成纤维细胞增殖反应增强的分子机制，通过定义调节增殖反应的细胞内信号通路和通过定义Thy-1表达对信号和增殖的影响; 2）通过比较Thy-1-/-基因靶向小鼠与野生型小鼠和嵌合Thy-1-/-小鼠（其中Thy-1的造血细胞表达已通过骨髓移植恢复）中的纤维化，来表征Thy-1表达在实验诱导的肺纤维化中的后果;和3）通过与对照组织中的成纤维细胞增殖和信号传导相比，探索来自经历肺移植的IPF患者的移植肺中的原位和离体成纤维细胞增殖和信号传导，来确定成纤维细胞Thy-1表达在特发性肺纤维化中的作用。了解成纤维细胞亚群在肺纤维化中的作用及其活化机制，可能为这种衰弱过程的新型细胞和途径特异性治疗干预提供理论基础。