This proposal investigates the role of proteinases and mediators in cutaneous pathophysiology. It is he product of years of productive collaboration between the principal investigators. The research attempts to define mechanisms by which various cell types interact under physiological and pathological conditions. Historically the central thrust began with an analysis of the role of proteinases in cutaneous pathophysiology. It now encompasses regulation of proteinase metabolism by cell differentiation, the role of proteinases in cellular behavior and the relationship of these enzymes to steroid and cytokine mediators in the cutaneous microenvironment. Our specific goals are to: (1) Establish the structure and function of the mast cell proteinases, chymase and tryptase, and determine their roles in cutaneous biology. (2) Define the regulatory effects of recombinant cytokines and steroid molecules on the phenotype and biosynthetic capability of dermal mast cell populations and their microenvironments. (3) Investigate the metabolism of the Plasminogen Activator- Plasmin system in keratinocyte biology utilizing biochemical, immunological and molecular biological methods. (4) Study the role of proteinases in disease states with special emphasis on understanding the modulation of proteinase activity in vivo and the effects of proteinase activation on tissue function. Special consideration will be given to: psoriasis, pemphigus, urticaria pigmentosum and diseases with evidence of mast cell activation. The complimentary areas of expertise of the participating scientists, the common theme of research, and the cordial atmostphere of cooperation and interaction insure that the whole is greater than the sum of its parts.
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