The chronic inflammafion 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 funcfion. 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 Acti, a novel E3 ublquifin Iigase, is an essenfial signaling molecule for IL-25 signal transducfion and is recruited to the IL-25R upon ligand sfimulafion. Interesfingly, Acti deficiency in epithelial cells effecfively attenuates IL-25-mediated allergic pulmonary inflammafion, and Acti deficiency in T cells also results in significanfiy diminished Th2 responses and lung inflammafion. Based on these findings, we hypothesize that the IL-25 induced Actlmediated signaling pathway is essenfial for Th2 cell responses and allergic pulmonary inflammafion through disfinct effects on epithelial and T cell compartments. To test this, we propose two Specific Aims. First, we invesfigate the mechanisfic role of IL-25-induced Acti-mediated signaling pathway in Th2 responses and allergic pulmonary inflammafion. Second, we determine the molecular mechanism by which Acti mediates IL-25 signaling. In accord with the translafional goals of our TPPG, we use the Informafion obtained in this project to develop decoy (inhibitory) peptides to disrupt the Acti-IL-25 receptor interaction. Decoy inhibitory pepfides in the IL-25 signal transduction pathway are explored as a new therapeutic strategy for allergic pulmonary inflammafion. Project 2 benefits significantly from interacfions with other projects in the TPPG, and relies heavily on TPPG Cores for resources such as human and murine ainway organotypic cultures. Altogether, the TPPG fosters the translation of Project 2 bench research studies to development of novel patient therapeufics.

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Cleveland Clinic Lerner
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