Type I collagen signaling in lung injury and fibrosis

肺损伤和纤维化中的 I 型胶原信号传导

• 批准号: 9308528
• 负责人: KEVIN KEEWOUN KIM
• 金额: $ 39.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308528
• 关键词: Alveolar; Animal Model; Apoptosis; Apoptotic; Architecture; Area; Attenuated; Cause of Death; Cell Death; Cell Survival; Cessation of life; Chronic Disease; Cicatrix; Clinical; Clinical Trials; Collagen; Collagen Type I; Complication; Coupled; Cultured Cells; Data; Deposition; Disease Progression; Epithelial Cells; Equilibrium; Event; Failure; Family; Feedback; Fibrillar Collagen; Fibroblasts; Fibrosis; Hamman-Rich syndrome; Human; Impairment; Inhibition of Apoptosis; Injury; Integrin alpha2; Integrins; Lead; Link; Lung; Mediating; Mediator of activation protein; Modality; Modeling; Mus; Organ; PTK2 gene; Pathologic; Pathway interactions; Physiological; Process; Production; Proteins; Pulmonary Fibrosis; Reagent; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Regulation; Research; Resolution; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Therapeutic Trials; Tissues; Transforming Growth Factor beta; Transgenic Mice; Translating; Tyrosine; Wound Healing; attenuation; crosslink; discoidin domain receptor 2; discoidin receptor; experimental study; feeding; human disease; in vivo; inhibitor/antagonist; injured; lung injury; mimetics; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; receptor; repaired; response; response to injury; targeted treatment

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.

标题：肺损伤和纤维化中的I型胶原蛋白信号传导 摘要/项目摘要 进行性纤维化是许多慢性疾病的并发症，总体上，器官纤维化是 美国的主要死因。尽管许多治疗策略已大大减弱了纤维化 将这些发现转化为IPF成功疗法的动物模型已被证明令人失望 几项阴性临床试验和两种新疗法仅适度降低了疾病的进展。一些 已经提出需要针对促纤维化途径不同部位的多模式疗法。 当前的范式是伤害启动动态修复过程，最终导致纤维纤维 胶原蛋白沉积和疤痕形成。进行性纤维化的特征是激活自我扩增 进料/正反馈信号传导途径导致过度疤痕。但是，无处不在 潜水员受伤后几乎所有组织的疤痕形成过程都表明疤痕也可能是 保护性限制正在进行的细胞和组织损伤，可能是解决初始损伤的必要条件。 尝试限制胶原蛋白沉积可能会导致最初煽动刺激的持续存在。更完整 理解进行性纤维化与分辨率之间涉及的链接机制 需要进行局灶性伤害刺激。 尽管纤维化过程中的基质信号传导已经研究了，但胶原蛋白I本身通常被认为是末端 我们发现胶原蛋白I也是进行性纤维化的关键介体。我们有 发现肺泡上皮细胞（AEC）凋亡是纤维化的必要且足够的引发剂 刚性胶原I矩阵对TGFβ的AEC凋亡反应钝化。在体内，我们发现胶原蛋白I表达 受伤后早期诱导，胶原蛋白I缺陷小鼠患有肺损伤和更大的死亡。 胶原I信号还可以增强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亲属酶家族，盘状结构域受体（DDR）。我们的 初步数据支持α2β1整合素和DDR2在调节中的重要和非冗余角色 这种损伤/纤维化周期。那是I型胶原蛋白可能在确定对伤害的反应中很重要 有限的疤痕形成与进行性纤维化是有限的，并有可能建立一个困境，其中失败的失败 在持续TGFβ诱导的AEC凋亡的背景下，纤维化可能导致更大的损伤焦点和 对纤维化途径的次优抑制作用。我们的中心假设是I型胶原蛋白信号促进 纤维化的传播和AEC凋亡的抑制作用，但这些过程受到不同途径的调节。 我们将进行旨在了解胶原蛋白I及其接收器的机理的研究 AEC凋亡和成纤维细胞使用当前在我们的实验室中可用的试剂（主要鼠）激活 人类解剖的AEC和​​成纤维细胞，正常人和IPF肺的脱细胞肺基质 以及受损伤的转基因小鼠的肺，以及使用新型转基因小鼠的体内实验。