Fibroblast control of TGF-beta activation by Thy-1 and lung fibrosis

Thy-1 成纤维细胞对 TGF-β 激活的控制和肺纤维化

• 批准号: 7176258
• 负责人: JOANNE E MURPHY-ULLRICH
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176258
• 关键词: Fibroblast; control; TGF; beta; activation; Fibroblast; control; TGF; beta; activation

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis is a rare and progressive, fatal disease for which there is no effective treatment. Dysregulated wound healing by subsets of fibrogenic lung fibroblasts leads to fibrosis in idiopathic pulmonary fibrosis. TGF-( is a key regulator of wound healing responses and its action is critical for fibrogenic progression. TGF-( must be activated from its latent state to affect these responses. Our data show that one of the differential characteristics of fibroblast subsets is the capacity to activate latent TGF-( in response to injury. The presence of the GPI-anchored protein, Thy-1, on lung fibroblasts limits the ability to activate TGF-(. These data suggest that Thy-1 is a biological response modifier which limits TGF-( activation. Thy-1 (-) fibroblasts express higher levels of the latent TGF-( binding protein 4 (LTBP-4) when stimulated with bleomycin than do Thy-1 (+) cells, consistent with the increased TGF-( activity in the lungs of LTBP-4 hypomorphic mice. Thy-1 (-) LTBP-4 hypomorphic lung fibroblasts fail to activate latent TGF-( in response to bleomycin, suggesting that LTBP-4 is necessary for the ability of Thy-1 (-) cells to respond. Since TGF-( activity is critical to the fibrogenic progression of pulmonary fibrosis, the capacity of interstitial fibroblasts to activate latent TGF-( could be a key determinant of either benign resolution of lung injury or the development of fibrotic complications. We hypothesize that the ability of pulmonary fibroblasts to activate latent TGF-( in response to stimulation is critical to fibrogenic progression following lung injury. Thus fibroblasts with attenuated TGF-( activation would favor limited wound healing responses, whereas, fibroblasts that exhibit robust TGF-( activation in response to injury would favor fibrogenic responses. The overall goal of this proposal is to determine how modulating TGF-( activation by lung fibroblasts affects progression of pulmonary fibrosis. We will use a novel strategy that employs a modified adenovirus and a fibroblast-specific promoter to drive fibroblast specific transgene expression of Thy-1 and LTBP-4 in vivo to test the effects of fibroblast-specific expression of these proteins on fibrogenic progression in a mouse model of bleomycin-induced pulmonary fibrosis. We propose the following aims: Specific Aim 1: To test the hypothesis that fibroblast-specific over-expression of Thy-1 protects from bleomycin-induced pulmonary fibrosis by limiting TGF-( activation and to determine if expression of constitutively active TGF-( abrogates the potential protective effects of Thy-1 overexpression; Specific Aim 2: To test the hypothesis that fibroblast expression of LTBP-4 is necessary for activation of latent TGF-( in vitro and whether LTBP-4 abrogates Thy-1 protection in vivo. These studies will provide new insights into how lung fibroblast subpopulations determine fibrogenic progression and potentially identify new therapeutic approaches to treat idiopathic pulmonary fibrosis.

描述（由申请人提供）：特发性肺纤维化是一种罕见而进行的致命疾病，没有有效的治疗方法。纤维化肺成纤维细胞亚群的伤口愈合失调导致特发性肺纤维化的纤维化。 TGF-（是伤口愈合反应的关键调节剂，其作用对于纤维纤维的进展至关重要。TGF-（必须从其潜在状态激活以影响这些反应。我们的数据表明，成纤维细胞亚群的差异特征之一是激活潜在的TGF-对损伤的响应（对损伤的效果。激活TGF-（。这些数据表明THY-1是一种生物反应修饰剂，限制TGF-（激活。THY-1（ - ）成纤维细胞表达更高水平的潜在TGF-（结合蛋白4（LTBP-4），当用Bleosycin刺激的比Do Thyy-1（+）细胞（+）细胞（+）细胞一致（+）一致（+）一致（+）一致（+）均一致（+）一致（+）的活性。小鼠。THY-1（ - ）LTBP-4低形态肺成纤维细胞无法激活潜在的TGF-（响应博霉素，这表明LTBP-4对于THY-1（ - ）细胞的能力是必不可少的。 TGF-（可能是肺部损伤良性分辨率或纤维化并发症发展的关键决定因素。 We hypothesize that the ability of pulmonary fibroblasts to activate latent TGF-( in response to stimulation is critical to fibrogenic progression following lung injury. Thus fibroblasts with attenuated TGF-( activation would favor limited wound healing responses, whereas, fibroblasts that exhibit robust TGF-( activation in response to injury would favor fibrogenic responses. The overall goal of this proposal is to determine how modulating TGF-( activation by lung fibroblasts affects progression of pulmonary fibrosis. We will use a novel strategy that employs a modified adenovirus and a fibroblast-specific promoter to drive fibroblast specific transgene expression of Thy-1 and LTBP-4 in vivo to test the effects of fibroblast-specific expression of these proteins on fibrogenic progression in a mouse博来霉素诱导的肺纤维化模型。具体目的2：要检验LTBP-4成纤维细胞表达的假说对于激活潜在TGF-是必要的（体外和LTBP-4是否消除了体内THY-1的保护。这些研究将提供有关肺成纤维细胞亚群如何确定纤维化进展的新见解，以确定纤维化进度和潜在的启动式培养精神，以识别新的IDII IDII。