The Role of JNK in Allergen-Induced Airway Remodeling

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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.