SIGNALING IN EPITHELIAL INJURY, PROLIFERATION & FIBROSIS

上皮损伤、增殖中的信号传导

• 批准号: 6758551
• 负责人: Brooke Taylor Mossman
• 金额: $ 154.6万
• 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/6758551
• 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部疾病的发展和/或修复至关重要。了解肺上皮细胞中发生的细胞信号传导级联反应及其与这些上皮结果的因果关系对于理解发病机理以及这些疾病和治疗策略至关重要。这些疾病和治疗策略的程序发病机理中要解决的中心假设。该程序项目要解决的中心假设是，在过敏性气道高反应/纤维化和石棉病模型中，有丝分裂原激活的蛋白激酶（MAPK）级联反应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/反式激活中及其在鼠类上皮细胞增殖中各自的作用在鼠类吸收模型中的上皮细胞增殖中的作用。项目＃2（IRVIN）检验了以下假设：在过敏性气道纤维化模型中，细支气管上皮细胞中的核因子-Kappab（NF-KAPPAB）在炎症中起发挥作用，这是炎症的结果，是炎症和阳离子蛋白质通过MAP触发上皮patheraile的造成阳离子蛋白的影响。项目＃3（Jaken）将阐明PKC在石棉鼠模型中PKC在MAPK途径，AP-1反式激活和上皮细胞增殖中的作用。最后，使用这两种模型的纤维化模型，项目＃4（Heintz）将通过一种新型的细菌人造染色体（BAC）基因转移技术检验假设，即可以通过表达Cyclin D1和Origin wilens许可因子CDC6来区分细胞增殖的MAPK级联反应。行政核心（Mossman），吸入/转基因小鼠核心（Hemenway/Rincon）和细胞成像和分析核心（TAATJES）对所有项目的成功至关重要。所有项目和核心领导者都有现有的研究合作和共同撰写的出版物。这个多学科的团队包括细胞和分子生物学家，生理学家，吸入毒理学家，生物统计学家以及转基因小鼠发展方法的专家。