Novel strategies for asthma therapy by regulating mast cell signaling by MyD88

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DESCRIPTION (provided by applicant): Asthma is a complex airway inflammatory disease characterized by bronchoconstriction, airway hyperresponsiveness and inflammation. There is a substantial body of evidence that demonstrates an important role for mast cell high affinity IgE receptor (FceRI) in the pathogenesis of asthma. Therefore, tremendous efforts have been directed towards understanding the signaling pathway via which function of this receptor is regulated. Emerging evidence suggests that epithelial cell-derived cytokine such as interleukin-33 (IL-33) and bacterial lipopolysaccharide (LPS) play important roles in asthma exacerbation via the activation of their respective receptors ST2 and TLR4 but the mechanisms of their action remains unknown. Myeloid differentiation factor (MyD) 88 is the most proximal adapter molecule that transmits signal for both IL-33 and LPS. We made the novel observation that MyD88 not only regulates IL-33 and LPS signaling in mast cells, it also contributes to antigen/IgE-mediated protein kinase B (Akt) phosphorylation and cytokine production. We also found that LPS or IL-33 synergizes with antigen/IgE for cytokine generation and that this cross-talk is almost abolished in MyD88-/- mast cells. Based on these findings, we hypothesize that MyD88 promotes allergic inflammation by regulating and cross-regulating Fc5RI signaling in mast cells. Two specific aims are proposed to further explore the role of MyD88 on mast cell signaling in vitro and murine model of allergic inflammation in vivo. In aim #1, we will use retrovirus to transfect MyD88-/- mast cells with wild-type or genetically modified MyD88 to delineate how this adapter molecule regulates and cross-regulates FceRI signaling in mast cells. In aim #2, we will first test the hypothesis that MyD88 expressed in mast cells mediates allergic inflammation in vivo. We will then modulate MyD88 signaling in mast cells and determine the impact of this modulation on allergic inflammation. We believe that proposed studies will generate significant new information on the regulation and cross-regulation of FceRI signaling in mast cells and may offer novel therapeutic approaches for the treatment of asthma and other allergic diseases. PUBLIC HEALTH RELEVANCE: Asthma is a complex airway inflammatory disease characterized by bronchoconstriction, airway hyperresponsiveness and inflammation. Approximately 17 million Americans are estimated to have asthma, one third of them children. In recent years, asthma prevalence and severity have been increasing dramatically world-wide. Mast cells release inflammatory mediators that cause the symptoms of asthma and other allergic diseases. This proposal is based on the identification of a new molecule that regulates mast cell function. We believe that proposed studies will generate significant new information on the regulation of mast cell function and may offer novel therapeutic approaches for the treatment of asthma and other allergic diseases.