The Role of JNK in Allergen-Induced Airway Remodeling

描述(申请人提供)：这项建议的假设是，在过敏性呼吸道疾病的小鼠模型中，JNK的激活是气道重塑和气道高反应性(AHR)发展所必需的，更具体地说，是呼吸道上皮细胞的激活。此外，我们假设转化生长因子-b通过转录因子c-jun和Smad3的磷酸化来激活JNK，从而增加结缔组织生长因子(CTGF)的表达，结缔组织生长因子是关键的促纤维化介质(模型)。这些假设将在两个具体目标中得到检验。具体目标1将直接阐述JNK在过敏原诱导的过敏性气道重塑中的作用，使用JNK1和JNK2缺失小鼠。上皮依赖性JNK激活的作用将在转基因小鼠中进行评估。特异性目的2将在体外和体内检测JNK缺失对转化生长因子-b诱导的信号转导事件的影响，并确定JNK依赖的c-jun与Smad2和Smad3的磷酸化在CTGF转录激活中的作用。这项研究的结果将更好地确定JNK信号通路在小鼠哮喘模型肺纤维化发展中的作用。

DESCRIPTION (provided by applicant): The hypothesis of this proposal is that activation of JNK in the lung, and more specifically the airway epithelium, is required for the development of airway remodeling and airway hyperresponsiveness (AHR) in a murine model of allergic airway disease. Furthermore, we hypothesize that JNK activation is required for the pro-fibrotic effects of TGF-b, by phosphorylation of the transcription factors c-Jun and Smad 3, resulting in increased expression of connective tissue growth factor (CTGF), a key pro-fibrotic mediator (model). These postulates will be tested in two specific aims. Specific Aim 1 will directly address the role of JNK in allergen induced allergic airway remodeling using JNK 1 and JNK 2 null mice. The role of epithelial dependent JNK activation will be assessed in a transgenic mouse. Specific Aim 2 will examine the impact of JNK deletion on TGF-b induced signaling events both in vitro and in vivo and define the role of JNK dependent phosphorylation of c-Jun versus smad 2 and smad 3 an the impact on the transcriptional activation of CTGF . The outcome of this study will better define the role of the JNK signaling pathway in the development of pulmonary fibrosis in a murine asthma model.