The chronic inflammation in asthma is due largely to the persistence of Th2 lymphocytes and Th2 cytokines/chemokines produced by both the structural cells of the lung as well as the infiltrating CD4+ lymphocytes, eosinophils, and basophils and the resident mast cells, leading to progressive loss of lung function. Recent studies have shown that IL-25 functions as an important mediator of Th2 responses and lies upstream of the classical Th2 cytokine responses. We recently discovered that Act1, a novel E3 ubiquitin Iigase, is an essential signaling molecule for IL-25 signal transduction and is recruited to the IL-25R upon ligand stimulation. Interestingly, Act1 deficiency in epithelial cells effectively attenuates IL-25-mediated allergic pulmonary inflammation, and Act1 deficiency in T cells also results in significantly diminished Th2 responses and lung inflammation. Based on these findings, we hypothesize that the IL-25 induced Act1 mediated signaling pathway is essential for Th2 cell responses and allergic pulmonary inflammation through distinct effects on epithelial and T cell compartments. To test this, we propose two Specific Aims. First, we investigate the mechanistic role of IL-25-induced Act1-mediated signaling pathway in Th2 responses and allergic pulmonary inflammation. Second, we determine the molecular mechanism by which Act1 mediates IL-25 signaling. In accord with the translational goals of our TPPG, we use the Information obtained in this project to develop decoy (inhibitory) peptides to disrupt the Acti-IL-25 receptor interaction. Decoy inhibitory peptides in the IL-25 signal transduction pathway are explored as a new therapeutic strategy for allergic pulmonary inflammation. Project 2 benefits significantly from interactions with other projects in the TPPG, and relies heavily on TPPG Cores for resources such as human and murine airway organotypic cultures. Altogether, the TPPG fosters the translation of Project 2 bench research studies to development of novel patient therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL103453-03
Application #
8478184
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$393,181
Indirect Cost
$139,568
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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