Type I collagen signaling in lung injury and fibrosis

标题：肺损伤和纤维化中的I型胶原信号传导 摘要/项目摘要 进行性纤维化是许多慢性疾病的并发症，并且总的来说，器官纤维化是慢性疾病的并发症。 是美国的主要死亡原因。尽管许多治疗策略已经显著地减弱了肝纤维化， 事实证明，将这些发现转化为成功的IPF疗法的动物模型令人失望， 几项阴性临床试验和两种新疗法只能适度减缓疾病的进展。一些 已经表明需要靶向促纤维化途径的不同部分的多模态疗法。 目前的范式是，损伤启动了一个动态修复过程，最终导致纤维化。 胶原沉积和瘢痕形成。进行性纤维化的特征在于自放大的 前馈/正反馈信号通路导致过度瘢痕形成。然而， 几乎每个组织的不同损伤后的瘢痕形成过程表明， 在限制正在进行的细胞和组织损伤方面具有保护性，并且可能是解决初始损伤所必需的。 试图限制胶原沉积可能会导致持续的初始刺激。更完整 了解进行性纤维化和消退之间平衡的相关机制 是必要的 虽然已经研究了纤维化过程中的基质信号传导，但I型胶原本身通常被认为是一个终点， 但是我们已经发现胶原蛋白I也是进行性纤维化的关键介质。我们有 发现肺泡上皮细胞（AEC）凋亡是纤维化的必要和充分的启动剂， 刚性胶原I基质减弱AEC对TGFβ的凋亡反应。在体内，我们发现I型胶原表达 在损伤后早期诱导，胶原蛋白I缺陷小鼠具有持续的肺损伤和更大的死亡。 胶原蛋白I信号传导还增强成纤维细胞募集和活化。胶原蛋白可以通过 特异性整联蛋白以及受体酪氨酸激酶家族，盘状结构域受体（DDR）。我们 初步数据支持α2β1整联蛋白和DDR2在调节 这种损伤/纤维化循环。因此，I型胶原可能在确定对损伤的反应是否 是有限的瘢痕形成与进行性纤维化，并可能建立一个困境，其中失败的 在持续的TGFβ诱导的AEC凋亡的背景下，纤维化可能导致更大的损伤灶， 促纤维化途径的次优抑制。我们的中心假设是I型胶原蛋白信号促进了 纤维化的传播和AEC凋亡的抑制，但这些过程是由不同的途径调节。 我们将继续进行旨在了解I型胶原及其受体在调节 AEC凋亡和成纤维细胞活化，使用我们实验室目前可用的试剂，包括原代小鼠 和人患病AEC和成纤维细胞，来自正常人和IPF肺的脱细胞肺基质， 以及来自受伤的转基因小鼠的肺，再加上使用新的转基因小鼠的体内实验。

Title: Type I collagen signaling in lung injury and fibrosis Abstract/Project Summary Progressive fibrosis is a complication of many chronic diseases and collectively, organ fibrosis is the leading cause of death in the US. Although many therapeutic strategies have dramatically attenuated fibrosis in animal models translating these findings into successful therapies for IPF has proven disappointing with several negative clinical trials and two new therapies only modestly slowing the progression of disease. Some have suggested the need for multi-modality therapies targeting different parts of the pro-fibrotic pathway. The current paradigm is that injury initiates a dynamic repair process that ultimately leads to fibrillar collagen deposition and scar formation. Progressive fibrosis is characterized by activation of self-amplifying feed-forward/positive feedback signaling pathways leading to excessive scarring. However, the ubiquity of the scar formation process after diverse injuries in nearly every tissue suggests that scarring may also be protective in limiting ongoing cellular and tissue damage and may be necessary to resolve the initial injury. Attempt at limiting collagen deposition may lead to persistence of the initial inciting stimuli. A more complete understanding into the linked mechanisms involved in the balance between progressive fibrosis and resolution of focal injurious stimuli is necessary. While matrix signaling during fibrosis has been studied, collagen I itself is often regarded as an end product of fibrosis but we have found that collagen I is also a critical mediator of progressive fibrosis. We have found that alveolar epithelial cell (AEC) apoptosis is a necessary and sufficient initiator of fibrosis and that a rigid collagen I matrix blunts the AEC apoptotic response to TGFβ. In vivo, we found that collagen I expression is induced early after injury and collagen I-deficient mice have sustained lung injury and greater death. Collagen I signaling also enhances fibroblast recruitment and activation. Collagen can initiate signaling through specific integrins as well as a family of receptor tyrosine kinsases, the discoidin domain receptors (DDR). Our preliminary data support important and non-redundant roles for both α2β1 integrin and DDR2 in regulation of this injury/fibrosis cycle. Thus, type I collagen is likely important in determining whether the response to injury is limited scar formation versus progressive fibrosis and potentially establishes a dilemma in which failure of fibrosis in the context of continued TGFβ-induced AEC apoptosis could lead to greater foci of injury and suboptimal inhibition of profibrotic pathways. Our central hypothesis is type I collagen signaling promotes both propagation of fibrosis and inhibition of AEC apoptosis but these processes are regulated by distinct pathways. We will pursue studies aimed at understanding the mechanism of collagen I and its receptors in regulation of AEC apoptosis and fibroblast activation using reagents currently available in our lab including, primary murine and human diseased AECs and fibroblasts, decellularized lung matrix from normal human and IPF lungs as well as lungs from injured transgenic mice, coupled with in vivo experiments using novel transgenic mice.