The goal of this proposal is to acquire an enhanced understanding of the cellular and molecular events responsible for the generation of Th2 inflammatory responses in the lung and their chronic effector mechanisms. Four hypotheses underlie this application. They are: (1) The predisposition of the lung to mount Th2 inflammatory responses to antigen is due to unique features of pulmonary dendritic cells; (2) Th1/Th2 cell balance in the lung is determined by the relative balance of the transcriptional regulators GATA-3 and T-bet, which are modulated by cytokine/chemokine signaling and co-stimulatory molecules; and (3) IL-13 mediates its effects via complex interactions with IL-13 receptor subunits and a cascade of target genes. Four projects in this application will focus on these issues. They are: (1) unique role of lung dendritic cells in Th2 responses - These studies will define the dendritic cells in the lung and the mechanisms by which they predispose to Th2 inflammation; (2) roles of ICOS in allergic airway responses - This project will explore the mechanisms by which ICOS regulates the production of IL-4, IL-13 and IgE; (3) Th2 differentiation and the GATA-3/ T-bet balance in regulating Th2/Th2 polarization; and (4) mechanisms of IL-13-induced inflammation and fibrosis - These studies will evaluate the in vivo ability of IL-13 to regulate the expression of IL-13 receptor subunits and selected target genes and the contributions that these moieties make to the IL-13 phenotype. This PPG also includes a Pathology Core, a Transgenic and Gene Targeting Core, a Lung Physiology Core, and an Administrative Core. Interactions between the projects and cores and amongst the investigators will lead to exciting new information regarding the pathogenesis of Th2 inflammation in asthma.
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