Role of Smad3 in obiliterative bronchiolitis

描述（由申请人提供）： 闭塞性细支气管炎（OB）被认为是肺移植受者慢性同种异体移植物功能障碍的表现，是一种不可逆的纤维增生过程，是长期生存的主要障碍。因此，针对确定肺移植受者中OB发展所涉及的因素的研究对于为这种无法治愈的疾病找到有效治疗方法至关重要。我们已经发现，转化生长因子-β（TGF β）通过其信号转导，SmadS，是必要的OB的发展，以及伴随OB的肌成纤维细胞转分化。因此，我们专注于调节TGF β/Smad信号在OB的机制，并取得了一些关键的意见。首先，细胞外半胱氨酸-胱氨酸（Cys/CySS）氧化还原对的氧化诱导TGF β和SrnadS的上调和活化。第二，肺成纤维细胞中SmadS表达和DNA结合，以及因此的肌成纤维细胞转化，通过异常的过渡基质组分，例如，纤连蛋白和I型胶原蛋白，它们总是在OB的环境中发现。第三，核转录因子过氧化物酶体增殖物激活受体-γ（PPARy）的激活通过破坏SmadS依赖性基因转录来抑制TGF β 1诱导的肌成纤维细胞转分化。这些发现使我们假设气道成纤维细胞中TGF β 1/Smad 3信号传导的激活是OB中肌成纤维细胞转分化的关键驱动因素，其通过慢性细胞外氧化应激、异常过渡基质和有缺陷的PPARy信号传导的存在而增强。该假设将在成纤维细胞培养物和OB实验模型中进行测试，旨在实现以下三个特定目标：1）检查慢性细胞外氧化应激通过Cys/CySS氧化还原对在体外和体内激活TGF β 1/Smad 3依赖性信号传导事件的机制2）检查过渡基质如何通过整合素依赖性信号促进TGF β 1/Smad 3信号传导和肌成纤维细胞转分化的激活3）确定PPARy影响SmadS信号通路和诱导实验OB中肌成纤维细胞转分化和基质表达的机制。这些复杂的问题将在专家顾问和合作者的帮助下得到解决，其更广泛的目标是揭示新的治疗目标。 (End摘要）

DESCRIPTION (provided by applicant): Obliterative bronchiolitis (OB), considered to be a manifestation of chronic allograft dysfunction in lung transplant recipients, is an irreversible fibroproliferative process that represents the major barrier to long term survival. Hence, research directed at identifying the factors involved in the development of OB in lung transplant recipients is paramount to finding effective treatment for this otherwise untreatable disease. We have found that Transforming Growth Factor-p (TGFp) via its signal transducer, SmadS, is necessary for the development of OB as well as the myofibroblast transdifferentiation that accompanies OB. Hence, we have focused on the mechanisms regulating TGFp/Smad signaling in OB and have made a number of key observations. First, oxidation of the extracellular cysteine-cystine (Cys/CySS) redox couple induces upregulation and activation of TGFp and SrnadS. Second, SmadS expression and DNA binding in lung fibroblasts, and consequently, myofibroblast transformation, is augmented by aberrant transitional matrix, components, e.g., fibronectin and type I collagen, which are invariably found in the setting of OB. And third, activation of the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy), inhibits TGFpl -induced myofibroblast transdifferentiation by disrupting SmadS-dependent gene transcription. These findings led us to the hypothesis that activation of TGFp1/Smad3 signaling in airway fibroblasts is a critical driver of myofibroblast transdifferentiation in OB that is intensified by the presence of chronic extracellular oxidant stress, aberrant transitional matrices, and defective PPARy signaling. This hypothesis will be tested in fibroblast cultures and in experimental models of OB in three specific aims designed to: 1) examine the mechanisms by which chronic extracellular oxidative stress activates TGFp1/Smad3-dependent signaling events in vitro and in vivo through the Cys/CySS redox couple 2) examine how transitional matrices promote activation of TGFpl /SmadS signaling and myofibroblast transdifferentiation through integrin-dependent signals 3) determine the mechanisms by which PPARy affects the SmadS signaling pathway and the induction of myofibroblast transdifferentiation and matrix expression in experimental OB. These complex issues will be addressed with the assistance of expert advisors and collaborators with the broader objective of unveiling novel targets for therapy. (End of Abstract)