PILOT--GENERATION OF CUTANEOUS MAST CELL DEFICIENT MICE

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Normal skin is a rich source of mast cells. Because mast cells release a diverse array of biologically active molecules (including cytokines, leukotrienes, prostaglandins, and proteases) when activated through their high affinity IgE receptors, they are believed to play a central role in certain cutaneous inflammatory responses such as urticaria. A major obstacle in addressing the role of the mast cell in other aspects of cutaneous pathophysiology is the absence of an animal model deficient in just mast cells. Recently we have identified a number of mast cell-specific genes that encode granule proteases. We have shown that mouse mast cell protease-5 (mMCP-5) and mouse mast cell carboxypeptidase-A (-A) are selectively expressed incutaneous mast cells. Using the promoter regions from these two genes encoding these enzymes linked to the diphtheria toxin gene we propose to generate transgenic mice which selectively lack cutaneous mast cells. In the first phase of this research, the 5" flanking regions of the mMCP-5 and mMCCP-A genes will be separately linked to the beta-galactosidase reporter gene. Transgenic mice will be generated to determine which 5' flanking region performs best in the reporter assay. In the second phase of the research, the 5' flanking region of the mMCP-5 gene or the mMCCP-A gene will be linked to the wild-type or mutated diphtheria toxin gene to generate transgenic mice deficient in cutaneous mast cells. The resulting animals will then be characterized. These will provide a powerful reagent for future studies that address the role of mast cells in normal and pathologic skin.