NF-KB ACTIVATION BY BRONCHIOLAR EPITHELIUM IN ASTHMA

在这项建议中要研究的假设是，在过敏性哮喘小鼠模型中观察到的病理表型的发展中，转录因子核因子-kappaB(NF-kappaB)在传导气道上皮细胞中的激活起着主动作用。这一假设将在3个具体目标上进行检验。具体目标1将确定变应原攻击后细支气管上皮中核因子-kappaB活化的时间进程，以及与炎症诱导和肺功能改变的相关性。具体目标2将是检测免疫和过敏原攻击后细支气管上皮细胞中核因子-kappaB调节基因RANTES、eoaxin和IL-6的mRNA和蛋白表达。最后，具体的目标3将是确定抑制核因子-kappaB的激活，使用只在细支气管上皮中表达IkappaBalpha超级抑制子的转基因小鼠，是否可以防止与哮喘相关的炎症反应的产生和肺生理的改变。这些研究的结果将证明在过敏性哮喘的发生发展中，细支气管上皮细胞中的核因子-kappaB信号级联的重要性。这些知识将为设计更有效的过敏性哮喘和其他炎症性肺部疾病的治疗方法提供机制基础。

The hypothesis to be investigated in this proposal is that activation of the transcription factor, Nuclear Factor-kappaB (NF-kappaB), in epithelial cells of conducting airways plays an initiative role in the development of the pathologic phenotype observed in a murine model of allergic asthma. The hypothesis will be tested in 3 specific aims. Specific Aim number 1 will be to determine the time-course of NF-kappaB activation in bronchiolar epithelium following allergen challenge and correlation with induction of inflammation and alterations in pulmonary function. Specific Aim number 2 will be to examine the mRNA and protein expression of the NF-kappaB regulated genes RANTES, eotaxin, and IL-6 in bronchiolar epithelial cells following immunization and challenge with allergen. Finally, Specific Aim number 3 will be to determine whether inhibition of NF-kappaB activation, using a transgenic mouse expressing a IkappaBalpha superrepressor exclusively in bronchiolar epithelium, prevents the generation of inflammatory responses and alterations in pulmonary physiology associated with asthma. Results of these studies will demonstrate the importance of NF- kappaB signaling cascades in bronchiolar epithelium, in development of allergic asthma. This knowledge will provide the mechanistic foundation for the design of more effective therapies for allergic asthma and other inflammatory lung diseases.