T helper 2 (Th2) cells mediate immunity to parasites and promote allergic disease, while Th1 cells provide immunity to intracellular pathogens and initiate inflammation. IFN- plays a major role in Th1 responses but inhibits the development of Th2 cells, while IL-4 promotes Th2 immunity and inhibits Th1 differentiation. The transcription factors Stat1 and Stat6 are the key signaling molecules for the cytokines IFN- and IL-4 respectively. We have identified a novel transcriptional cofactor, CoaSt6 (Collaborator of Stat6) that specifically enhances Stat6 but not Stat1 dependent transcription. Owing to the presence of macro domains and the PARP (poly ADP-ribose polymerase) catalytic domain, CoaSt6 belongs to the PARP family of proteins and is also called PARP-14. We have demonstrated that CoaSt6/PARP-14 contains PARP catalytic activity and preliminary data shows that inhibition of PARP activity with a pharmacological inhibitor targets IL-4 but not IFN- mediated gene induction. Furthermore, the differentiation of T helper cells into the Th2 phenotype is less efficient in the presence of PARP inhibitors. Our preliminary data also demonstrates that the intranasal administration of a PARP inhibitor to a mouse model of asthma reduces inflammation in the lung. The goal of this application is to elucidate the molecular mechanism by which CoaSt6/PARP-14 functions and to determine its role in T helper cell mediated immunity. The hypothesis for this proposal is that the macro and PARP domains of CoaSt6/PARP-14 employ a unique mechanism to regulate transcription and, the requirement of PARP activity for Th2 responses can be used as a therapeutic target for asthma. To address this hypothesis we will employ biochemical and molecular biological tools to define the mechanism by which CoaSt6/PARP-14 regulates transcription. Using a murine model we will determine the role of CoaSt6/PARP-14 in Th2 mediated allergic asthma. Further, we will investigate if inhibition of PARP activity in a mouse model of atopic airway hyperresponsiveness is able to alleviate this disease. Taken together, the proposed studies are aimed to understand the biological function of a novel transcriptional cofactor and will in fact test the feasibility of a therapy for allergic asthma.
Current treatments for asthma include administration of glucocorticoids and leukotriene antagonists, which target the inflammatory response that cause the symptoms of asthma. It is known that T helper cells of the immune system play a critical role in the initiation and the progression of the asthmatic condition. The overall goal of this project is to develop a therapy for asthmatic patients by targeting their T helper cell responses that are responsible for the initiation of the asthmatic condition.
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