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: 7341144
• 负责人: JOANNE E MURPHY-ULLRICH
• 金额: $ 21.75万
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341144
• 关键词: Adenoviruses; Affect; Attenuated; Benign; Binding Proteins; Biological Response Modifiers; Bleomycin; Cells; Characteristics; Data; Development; Disease; Exhibits; Fibroblasts; Fibrosis; Goals; Hamman-Rich syndrome; In Vitro; Lung; Mus; Protein Overexpression; Proteins; Pulmonary Fibrosis; Resolution; Testing; Transforming Growth Factor beta; Wound Healing; in vivo; insight; interstitial; lung injury; mouse model; novel strategies; novel therapeutics; promoter; protective effect; protein expression; response; response to injury; transgene expression

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的进行性致命疾病，目前尚无有效的治疗方法。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。 TGF-( 是伤口愈合反应的关键调节因子，其作用对于纤维化进展至关重要。TGF-( 必须从其潜伏状态被激活才能影响这些反应。我们的数据表明，成纤维细胞亚群的差异特征之一是能力激活潜在的 TGF-( 以应对损伤。肺成纤维细胞上 GPI 锚定蛋白 Thy-1 的存在限制了激活 TGF-( 的能力。这些数据表明 Thy-1 是一种生物反应调节剂这限制了 TGF-( 激活。当用博莱霉素刺激时，Thy-1 (-) 成纤维细胞表达的潜在 TGF-( 结合蛋白 4 (LTBP-4) 水平高于 Thy-1 (+) 细胞，这与 TGF-β 增加一致-( LTBP-4 低效型小鼠肺部的活性。Thy-1 (-) LTBP-4 低效型肺成纤维细胞无法激活潜在的 TGF-(博来霉素，表明 LTBP-4 对于 Thy-1 (-) 细胞的反应能力是必需的，因为 TGF-( 活性对于肺纤维化的纤维化进展至关重要，因此间质成纤维细胞激活潜在 TGF-( 的能力可能会增加)。是肺损伤良性解决或纤维化并发症发生的关键决定因素。我们假设肺成纤维细胞响应刺激而激活潜在 TGF-( 的能力对于肺损伤后的纤维化进展至关重要。因此，TGF-( 激活减弱的成纤维细胞将有利于有限的伤口愈合反应，而表现出强大 TGF-( 的成纤维细胞) ( 对损伤的激活将有利于纤维化反应。该提案的总体目标是确定肺成纤维细胞调节 TGF-( 激活如何影响肺纤维化的进展。我们将使用一种新策略，采用修饰的腺病毒和成纤维细胞特异性启动子来驱动 Thy-1 和 LTBP-4 体内成纤维细胞特异性转基因表达，以测试这些蛋白的成纤维细胞特异性表达对小鼠模型中纤维化进展的影响我们提出以下目标： 具体目标 1：检验 Thy-1 成纤维细胞特异性过度表达可预防博来霉素诱导的肺纤维化的假设。通过限制 TGF-( 激活来抑制纤维化，并确定组成型活性 TGF-( 的表达是否会消除 Thy-1 过表达的潜在保护作用；具体目标 2：检验以下假设：LTBP-4 的成纤维细胞表达对于体外激活潜在 TGF-( 以及 LTBP-4 是否在体内消除 Thy-1 保护是必需的。这些研究将为肺成纤维细胞亚群如何发挥作用提供新的见解确定纤维化进展并可能确定治疗特发性肺纤维化的新治疗方法。