SIGNALING IN EPITHELIAL INJURY, PROLIFERATION & FIBROSIS

上皮损伤、增殖中的信号传导

• 批准号: 6537952
• 负责人: Brooke Taylor Mossman
• 金额: $ 146.54万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537952
• 关键词: biological signal transduction; cell proliferation; interstitial lung diseases; mitogen activated protein kinase; respiratory epithelium

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.

气道和肺泡上皮细胞的激活、损伤和增殖对于纤维增生性肺病的发展和/或修复至关重要。了解肺上皮细胞中发生的细胞信号级联及其与这些上皮结果的因果关系对于了解发病机制以及这些疾病和治疗策略至关重要。本计划要解决的中心假设是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，丝裂原激活蛋白激酶（MAPK）级联与过敏性气道高反应性/纤维化和石棉肺模型中的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 (ERK) 和 c-Jun NH2 末端激酶 (JNK) 在 fos/jun（AP-1 家族成员）表达/反式激活中的作用及其各自的作用小鼠吸入石棉沉着模型中的上皮细胞增殖。项目#2 (Irvin) 测试了这样的假设：细支气管上皮细胞中核因子-kappaB (NF-kappaB) 的激活在过敏性气道纤维化小鼠模型的炎症中起起始作用，其结果是炎症和阳离子蛋白的形成通过 MAPK 途径引发上皮损伤。项目 #3 (Jaken) 将阐明 PKC 在石棉沉滞症小鼠模型中的 MAPK 通路调节、AP-1 反式激活和上皮细胞增殖中的作用。最后，项目 #4 (Heintz) 将使用两种纤维化模型，通过一种新型细菌人工染色体 (BAC) 基因转移技术来测试这一假设，即导致细胞增殖的 MAPK 级联激活可以与对细胞至关重要的激活区分开来。细胞周期蛋白 D1 和起源许可因子 cdc6 的表达造成的损伤。管理核心（Mossman）、吸入/转基因小鼠核心（Hemenway/Rincon）以及细胞成像和分析核心（Taatjes）对于所有项目的成功至关重要。所有项目和核心领导者都有预先存在的研究合作并共同撰写出版物。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。