Matrix Regulation of Pulmonary Fibrosis

肺纤维化的基质调节

• 批准号: 8302195
• 负责人: Carol Jiurong Liang
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302195
• 关键词: Basement membrane; CD44 Antigens; Cell surface; Cells; Data; Deposition; Development; Epithelial Cells; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Funding; Gases; Gene Expression Profile; Genomics; Glycosaminoglycans; Hamman-Rich syndrome; Hyaluronan; Injury; Interstitial Pneumonia; Invaded; Label; Laboratories; Lead; Lung; Lung Inflammation; Lung diseases; Medical; Mesenchymal; Mesothelium; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Pathologic; Phenotype; Population; Principal Investigator; Production; Pulmonary Fibrosis; Regulation; Relative (related person); Role; Signal Pathway; Smooth Muscle Actin Staining Method; Source; Testing; Transgenes; Transgenic Mice; Work; alveolar epithelium; base; extracellular; hyaluronan synthase 1; lung injury; mortality; mouse model; novel; overexpression; programs; promoter; receptor

DESCRIPTION (provided by applicant): The mechanisms that control severe and progressive pulmonary fibrosis remain poorly understood. This program has focused on elucidating the roles of the extracellular matrix in regulating lung inflammation and fibrosis in the context of non-infectious lung injury. Work from our laboratory during this period of funding has focused on the role of the extracellular glycosaminoglycan hyaluronan (HA) in regulating lung inflammation and fibrosis. We have identified distinct functions for HA depending on both the cellular context of its expression and the form in which it is presented to interacting cells. We have discovered that HA expressed on the cell surface of lung epithelial cells serves a protective function against non-infectious insults. In contrast, when myofibroblasts are directed to over-express hyaluronan synthase 2 (has2) under control of the alpha-smooth muscle actin promoter (ASMA-HAS2), the result is a severe and progressive fibrodestructive lung disease after injury that causes significant mortality. We have made the exciting observation that fibroblasts isolated from ASMA-HAS2 mice have an invasive phenotype. We have also generated the first mesenchymal-targeted deletion of has2 expression and found that both fibrosis and matrix invasion of fibroblasts is blunted. Based on these data we have generated the hypothesis that severe and progressive lung fibrosis requires the development of an invasive fibroblast phenotype dependent upon has2. We will test this hypothesis in the following Specific Aims: 1. Determine the roles of has2 in regulating progressive lung fibrosis and the development of an invasive fibroblast phenotype. 2. Determine the role of has2 in regulating the development of pulmonary fibrosis in TGF-¿ transgenic mice. 3. Determine the source of the invasive fibroblast phenotype using lineage labeling of alveolar epithelium, mesothelium and resident lung fibroblasts. 4. Identify genomic signatures of matrix-invading fibroblasts from severe pulmonary fibrosis and elucidate the signaling pathways that regulate invasion.

描述（由申请人提供）：控制严重和进行性肺纤维化的机制仍然知之甚少。该项目的重点是阐明细胞外基质在非感染性肺损伤背景下调节肺部炎症和纤维化的作用。在此资助期间，我们实验室的工作重点是细胞外糖胺聚糖透明质酸 (HA) 在调节肺部炎症和纤维化中的作用。我们根据其表达的细胞背景和其呈现给相互作用细胞的形式确定了 HA 的不同功能。我们发现肺上皮细胞表面表达的HA具有针对非感染性损伤的保护功能。相反，当肌成纤维细胞在α-平滑肌肌动蛋白启动子（ASMA-HAS2）的控制下过度表达乙酰透明质酸合酶2（has2）时，结果是损伤后出现严重的进行性纤维破坏性肺病，导致严重死亡。我们进行了令人兴奋的观察，即从 ASMA-HAS2 小鼠中分离的成纤维细胞具有侵袭性表型。我们还首次实现了 has2 表达的间充质靶向缺失，并发现成纤维细胞的纤维化和基质侵袭均减弱。基于这些数据，我们提出了这样的假设：严重的进行性肺纤维化需要依赖于 has2 的侵袭性成纤维细胞表型的发展。我们将在以下具体目标中检验这一假设： 1. 确定 has2 在调节进行性肺纤维化和侵袭性成纤维细胞表型发展中的作用。 2.确定has2在调节TGF-¿转基因小鼠肺纤维化发展中的作用。 3. 使用肺泡上皮、间皮和常驻肺成纤维细胞的谱系标记确定侵袭性成纤维细胞表型的来源。 4. 鉴定严重肺纤维化基质侵袭成纤维细胞的基因组特征，并阐明调节侵袭的信号通路。