Fibroblast Specific Protein 1 in Pulmonary Fibrosis

肺纤维化中的成纤维细胞特异性蛋白 1

• 批准号: 6538080
• 负责人: Timothy S. Blackwell
• 金额: $ 33.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6538080
• 关键词: calcium binding protein; cell population study; cell transformation; collagen; extracellular matrix; fibroblasts; fibrogenesis; intermediate filaments; laboratory mouse; molecular pathology; pathologic process; pulmonary fibrosis /granuloma; recombinant proteins; respiratory epithelium; transforming growth factors

Activated fibroblasts determine the extent of pulmonary fibrosis by their production of collagen and other matrix components. Fibroblast specific protein 1 (FSP1) is a member of the S100 protein superfamily and appears to play an early role in establishing the fibroblast phenotype. Although the origin of activated fibroblasts in pulmonary fibrosis is uncertain, recent studies in the kidney have shown that fibroblasts may arise from epithelium through a phenomenon called epithelial- mesenchymal transformation. Transforming growth factor-beta and other phenotypic modulators appear to regulate this process through up- regulation of FSP1 and other proteins that control fibroblast phenotype. In this project, we propose to investigate the following hypothesis. In lung fibrosis, activated lung fibroblasts are derived from airway epithelial cells as well as from resident interstitial fibroblasts. FSP1 is both a marker and important determinant of this cellular phenotype. The appearance and persistence of FSP1 expressing cells are crucial for determining the extent of lung fibrosis. We propose three specific aims: 1) to identify the role of FSP1+ cells in experimental lung fibrosis, 2) to determine whether epithelial-mesenchymal transformation occurs in the lungs and contributes to lung fibrosis in the mouse, 3) to modulate FSP1 expression and determine the effects on epithelial-mesenchymal transformation and induction of lung fibrosis. Identification of a more useful fibroblast marker in the lungs would allow identification and monitoring of this cell population after fibrogenic stimuli and could foster targeted treatments that alter the accumulation or function of cells exhibiting the fibroblast phenotype. In addition, we plan to explore the origins of lung fibroblasts in experimental lung fibrosis with the hope that determining the presence and extent of epithelial-mesenchymal transformation in the lungs in these models will lead to innovative interventions to inhibit or reverse this transformation, thus limiting fibrosis and lung dysfunction.

活化的成纤维细胞通过产生胶原蛋白和其他基质成分来确定肺纤维化的程度。成纤维细胞特异性蛋白 1 (FSP1) 是 S100 蛋白超家族的成员，似乎在建立成纤维细胞表型中发挥早期作用。尽管肺纤维化中活化的成纤维细胞的起源尚不清楚，但最近对肾脏的研究表明，成纤维细胞可能通过一种称为上皮间质转化的现象从上皮产生。转化生长因子-β 和其他表型调节剂似乎通过上调 FSP1 和其他控制成纤维细胞表型的蛋白质来调节这一过程。在这个项目中，我们建议研究以下假设。在肺纤维化中，活化的肺成纤维细胞源自气道上皮细胞以及驻留的间质成纤维细胞。 FSP1 既是该细胞表型的标记又是重要的决定因素。 FSP1 表达细胞的出现和持续存在对于确定肺纤维化的程度至关重要。我们提出了三个具体目标：1) 确定 FSP1+ 细胞在实验性肺纤维化中的作用，2) 确定上皮间质转化是否发生在肺部并导致小鼠肺纤维化，3) 调节 FSP1 表达并确定对上皮间质转化和诱导肺纤维化的影响。鉴定肺部中更有用的成纤维细胞标记物将允许在纤维形成刺激后识别和监测该细胞群，并可以促进改变表现出成纤维细胞表型的细胞的积累或功能的靶向治疗。此外，我们计划探索实验性肺纤维化中肺成纤维细胞的起源，希望确定这些模型中肺部上皮间质转化的存在和程度，将导致抑制或逆转这种转化的创新干预措施，从而限制纤维化和肺功能障碍。