Mast cells are well known for their inflammatory functions in allergy, and are suspected to participate in other autoimmune diseases. It appears that maintaining mast cell homeostasis is critical for preventing a range of inflammatory responses, but how this balance is achieved is not understood. Recently we found that Lyn KO mice exhibit mast cell hyperplasia, esoinophil infiltration and enhanced IgE and IgG receptor expression and signaling. Given the inflammatory functions of mast cells, we hypothesize that Lyn deficiency leads to chronic mast cell activation that results in eosinophil recruitment and subsequent inflammatory disease. We will directly test the role of mast cells in Lyn-associated inflammatory disease. These experiments will provide a novel means of approaching mast cell-associated disorders.
Our Specific Aims are: I. To determine the role of Lyn kinase in mast cell IgE and IgG receptor expression and function. II. To employ genetic approaches to directly measure the importance of mast cells and their associated mediators in the onset and progression of Th2 inflammatory disease. Study Design:
In Aim I, we will employ mouse and human mast cells in in vitro and in vivo models, to uncover how Lyn deficiency alters the expression and function of mast cell IgE and IgG receptors. We will specifically focus on how these changes alter eosinophil and regulatory T cell recruitment. We will also determine if Lyn expression is reduced in atopic patients.
In Aim II, we will create a series of double mutant mice to measure the importance of mast cells, IgE and FcyRIII in the onset and progression of the Th2 inflammatory disease caused by Lyn deficiency. We will also determine the necessary versus sufficient role of Lyn-deficient mast cells by trasplanting these cells into mast cell-deficient mice. These studies will be complemented by our collaborative interactions at VCU. With Drs. Spiegel, Kepley and Schwartz, we will expand our work to human mast cells. With Dr. Conrad Lyn KO mice will be studied in an asthma model system. Further, Drs. Spiegel and Chalfant will test the efficacy of their novel immunosuppressive compound on Lyn-deficient mast cells. Our studies will reveal the contributions made by Lyn kinase to inflammatory disease and offer new avenues for therapy.
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