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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL082121-02
Application #
7113601
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Rothgeb, Ann E
Project Start
2005-08-01
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Janssen-Heininger, Yvonne Mw; Irvin, Charles G; Scheller, Erich V et al. (2012) Airway Hyperresponsiveness and Inflammation: Causation, Correlation, or No Relation? J Allergy Ther 2012:
Alcorn, John F; Ckless, Karina; Brown, Amy L et al. (2010) Strain-dependent activation of NF-kappaB in the airway epithelium and its role in allergic airway inflammation. Am J Physiol Lung Cell Mol Physiol 298:L57-66
Alcorn, John F; van der Velden, Jos; Brown, Amy L et al. (2009) c-Jun N-terminal kinase 1 is required for the development of pulmonary fibrosis. Am J Respir Cell Mol Biol 40:422-32
Alcorn, John F; Guala, Amy S; van der Velden, Jos et al. (2008) Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-beta1. J Cell Sci 121:1036-45