Mast cells are well known for their inflammatory functions in allergy, and are suspected to participate inother autoimmune diseases. It appears that maintaining mast cell homeostasis is critical for preventing arange of inflammatory responses, but how this balance is achieved is not understood. Recently we foundthat Lyn KO mice exhibit mast cell hyperplasia, esoinophil infiltration and enhanced IgE and IgG receptorexpression and signaling. Given the inflammatory functions of mast cells, we hypothesize that Lyndeficiency leads to chronic mast cell activation that results in eosinophil recruitment and subsequentinflammatory 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 associatedmediators 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 Lyndeficiency alters the expression and function of mast cell IgE and IgG receptors. We will specifically focuson how these changes alter eosinophil and regulatory T cell recruitment. We will also determine if Lynexpression is reduced in atopic patients.
In Aim II, we will create a series of double mutant mice to measure the importance of mast cells, IgEand FcyRIII in the onset and progression of the Th2 inflammatory disease caused by Lyn deficiency. Wewill also determine the necessary versus sufficient role of Lyn-deficient mast cells by trasplanting thesecells 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 bestudied in an asthma model system. Further, Drs. Spiegel and Chalfant will test the efficacy of their novelimmunosuppressive compound on Lyn-deficient mast cells. Our studies will reveal the contributions madeby Lyn kinase to inflammatory disease and offer new avenues for therapy.
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