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

基本信息

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
项目类别：
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

项目摘要

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，总的来说，器官纤维化是尽管许多治疗策略已显着减轻纤维化。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一些阴性的临床试验和两种新疗法只能适度减缓疾病的进展。表明需要针对促纤维化途径的不同部分进行多模式治疗。当前的范例是启动动态修复过程，最终导致纤维化胶原沉积和疤痕形成的特征是自我放大的激活。然而，前馈/正反馈信号通路导致过度疤痕形成。几乎每个组织的不同损伤后的疤痕形成过程表明，疤痕也可能与对限制持续的细胞和组织损伤具有保护作用，并且可能是解决最初损伤所必需的。限制胶原蛋白沉积的尝试可能会导致最初的刺激刺激更加彻底。了解进行性纤维化和消退之间平衡所涉及的相关机制局部伤害性刺激的减少是必要的。虽然纤维化过程中的基质信号传导已被研究，但胶原蛋白 I 本身通常被视为纤维化的终点纤维化的产物，但我们发现 I 型胶原蛋白也是进行性纤维化的关键介质。发现肺泡上皮细胞（AEC）凋亡是纤维化的必要且充分的引发剂，并且刚性胶原蛋白 I 基质减弱了 AEC 对 TGFβ 的凋亡反应在体内，我们发现胶原蛋白 I 表达。损伤后早期诱导，缺乏 I 型胶原蛋白的小鼠会遭受肺损伤并导致更多死亡。 I 型胶原蛋白信号传导还可以增强成纤维细胞的募集和激活胶原蛋白可以通过以下方式启动信号传导。特定整合素以及受体酪氨酸激酶家族，我们的盘状结构域受体 (DDR)。初步数据支持 α2β1 整合素和 DDR2 在调节中的重要且非冗余的作用因此，I 型胶原蛋白对于确定是否对损伤做出反应可能很重要。有限的疤痕形成与进行性纤维化之间的关系，并可能造成一个两难的境地： TGFβ 持续诱导 AEC 凋亡背景下的纤维化可能导致更大的损伤灶和我们的中心假设是 I 型胶原蛋白信号传导促进这两种途径。纤维化的传播和 AEC 细胞凋亡的抑制，但这些过程由不同的途径调节。我们将进行旨在了解 I 型胶原蛋白及其受体调节的机制的研究使用我们实验室目前可用的试剂（包括原代小鼠）进行 AEC 凋亡和成纤维细胞激活以及人类患病的 AEC 和成纤维细胞，来自正常人类和 IPF 肺的脱细胞肺基质，如以及来自受伤转基因小鼠的肺，并结合使用新型转基因小鼠的体内实验。