The Role of JNK in Allergen-Induced Airway Remodeling

描述（由申请人提供）：本提案的假设是，在小鼠变应性气道疾病模型中，肺部，更具体地说是气道上皮中，JNK的激活是气道重塑和气道高反应性（AHR）发展所必需的。此外，我们假设TGF-b的促纤维化作用需要JNK激活，通过磷酸化转录因子c-Jun和Smad 3，导致结缔组织生长因子（CTGF）的表达增加，CTGF是促纤维化的关键介质（模型）。这些假设将在两个具体目标中得到检验。特异性Aim 1将直接解决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。Specific Aim 2将研究JNK缺失对体外和体内TGF-b诱导的信号事件的影响，并确定JNK依赖性c-Jun磷酸化对smad 2和smad 3的作用，以及对CTGF转录激活的影响。本研究的结果将更好地定义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.