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 摘要/项目摘要 进行性纤维化是许多慢性疾病的并发症，总的来说，器官纤维化是 在美国居死因首位。尽管许多治疗策略已经显著地减轻了 将这些发现转化为治疗IPF的成功疗法的动物模型被证明是令人失望的 几项阴性临床试验和两种新疗法只是略微减缓了疾病的进展。一些人 建议有必要针对促纤维化途径的不同部分进行多模式治疗。 目前的范式是，损伤启动了一个动态修复过程，最终导致纤维组织 胶原沉积和疤痕形成。进行性纤维化的特征是激活自我放大 前馈/正反馈信号通路导致过度疤痕。然而，无处不在的 几乎每个组织在不同损伤后的疤痕形成过程表明，疤痕也可能是 在限制正在进行的细胞和组织损伤方面具有保护性，可能是解决最初损伤所必需的。 限制胶原沉积的尝试可能会导致最初的刺激持续存在。一个更完整的 对进展性纤维化与消退之间平衡的相关机制的理解 局灶性伤害性刺激是必要的。 虽然纤维化过程中的基质信号已被研究，但I型胶原本身通常被认为是一个终点。 I型胶原是纤维化的产物，但我们发现I型胶原也是进行性纤维化的关键介质。我们有 研究发现，肺泡上皮细胞(AEC)的凋亡是纤维化的必要和充分的启动者，并且 硬质I型胶原基质可钝化血管内皮细胞对转化生长因子β的凋亡反应。在体内，我们发现I型胶原蛋白的表达 是在损伤后早期诱导的，而I型胶原蛋白缺陷小鼠则遭受了肺损伤和更大的死亡。 I型胶原信号也促进成纤维细胞的募集和激活。胶原蛋白可以通过 特定的整合素以及受体酪氨酸激酶家族，盘状结构域受体(DDR)。我们的 初步数据支持α2β1整合素和DDR2在调节 这一损伤/纤维化循环。因此，I型胶原在决定对损伤的反应中可能是重要的 是有限的瘢痕形成还是进行性的纤维化，并潜在地建立了一个两难境地，即 在转化生长因子β诱导血管内皮细胞持续凋亡的背景下的纤维化可导致更大的损伤灶和 对促纤维化途径的次优抑制。我们的中心假设是I型胶原信号促进两者 纤维化的传播和抑制血管内皮细胞的凋亡，但这些过程由不同的途径调节。 我们将继续进行研究，以了解I型胶原及其受体在调节 使用我们实验室现有试剂包括原代小鼠的AEC凋亡和成纤维细胞激活 和人病变的AECs和成纤维细胞，正常人和IPF肺脱细胞的基质 以及来自受损转基因小鼠的肺，再加上使用新型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.