SIGNALING IN EPITHELIAL INJURY, PROLIFERATION & FIBROSIS

气道和肺泡上皮细胞的激活、损伤和增殖对纤维增生性肺疾病的发展和/或修复至关重要。了解发生在肺上皮细胞中的细胞信号级联及其与这些上皮结果的因果关系对于理解这些疾病的发病机制和治疗策略至关重要。本课程的中心假设是解决这些疾病的发病机制和治疗策略。本项目要解决的中心假设是，在过敏性气道高反应性/纤维化和石棉肺模型中，丝裂原活化蛋白激酶（MAPK）级联与上皮细胞损伤和增殖有因果关系。项目#1 （Mossman）将定义细胞外信号调节激酶（ERKs）和c-Jun nh2末端激酶（JNKs）在fos/jun （AP-1家族成员）的表达/反激活中的作用，以及它们各自在石棉肺小鼠吸入模型中上皮细胞增殖中的作用。项目#2 （Irvin）验证了在小鼠过敏性气道纤维化模型中，细支气管上皮细胞中核因子-kappaB （NF- kappaB）的激活在炎症中起启动作用的假设，其结果是炎症和阳离子蛋白的细化，通过MAPK途径触发上皮损伤。项目#3 （Jaken）将阐明PKC在石棉肺小鼠模型中调控MAPK通路、AP-1反激活和上皮细胞增殖中的作用。最后，项目#4 （Heintz）使用这两种纤维化模型，将用一种新的细菌人工染色体（BAC）基因转移技术验证这一假设，即MAPK级联反应的激活导致细胞增殖，可以通过细胞周期蛋白D1和起源许可因子cdc6的表达来区分那些对细胞损伤至关重要的细胞。管理核心（Mossman），吸入/转基因小鼠核心（Hemenway/Rincon）和细胞成像和分析核心（Taatjes）将是所有项目成功的关键。所有项目和核心领导者都有先前的研究合作和共同撰写的出版物。这个多学科团队包括细胞和分子生物学家、生理学家、吸入毒理学家、生物统计学家和转基因小鼠开发方法专家。

Activation, injury and proliferation of airway and alveolar epithelial cells are critical to the development and/or repair of fibroproliferative lung diseases. Understanding the cell signaling cascades that occur in pulmonary epithelial cells and their causal relationship to these epithelial outcomes are vital to understanding the pathogenesis and these diseases and therapeutic strategies. The central hypothesis to be addressed in this Program pathogenesis of these diseases and therapeutic strategies. The central hypothesis to be addressed in this Program Project is that the mitogen-activated protein kinase (MAPK) cascades are causally linked to epithelial cell injury and proliferation in models of allergic airway hyperresponsiveness/fibrosis and asbestosis. Project #1 (Mossman) will define the role of extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs) in expression/transactivation of fos/jun (AP-1 family members) and their respective roles in epithelial cell proliferation in a murine inhalation model of asbestosis. Project #2 (Irvin) tests the hypothesis that activation of Nuclear Factor-kappaB (NF- kappaB) in bronchiolar epithelial cells plays an initiating role in inflammation in a murine model of allergic airway fibrosis, a consequence being inflammation and the elaboration of cationic proteins that trigger epithelial injury via MAPK pathways. Project #3 (Jaken) will elucidate the role of PKC in modulation of MAPK pathways, AP-1 transactivation, and epithelial cell proliferation in a murine model of asbestosis. Lastly, Project #4 (Heintz), using both models of fibrosis, will test the hypothesis, with a novel bacterial artificial chromosome (BAC) gene transfer technology, that activation of MAPK cascades leading to cell proliferation can be discriminated from those critical to cell injury by expression of cyclin D1 and the origin licensing factor cdc6. An Administrative Core (Mossman), an Inhalation/Transgenic Mouse Core (Hemenway/Rincon) and Cell Imaging and Analysis Core (Taatjes) will be critical to the success of all projects. All project and core leaders have pre-existing research collaborations and jointly authored publications. This multi-disciplinary team includes cell and molecular biologists, a physiologist, an inhalation toxicologist, a biostatistician, and an expert in approaches for development of transgenic mice.