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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR039674-03
Application #
3092436
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1988-12-15
Project End
1993-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schechter, Norman M; Plotnick, Michael I (2004) Measurement of the kinetic parameters mediating protease-serpin inhibition. Methods 32:159-68
Plotnick, Michael I; Rubin, Harvey; Schechter, Norman M (2002) The effects of reactive site location on the inhibitory properties of the serpin alpha(1)-antichymotrypsin. J Biol Chem 277:29927-35
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Ando, Y; Jensen, P J (1996) Protein kinase C mediates up-regulation of urokinase and its receptor in the migrating keratinocytes of wounded cultures, but urokinase is not required for movement across a substratum in vitro. J Cell Physiol 167:500-11
Margolis, D J; Kruithof, E K; Barnard, M et al. (1996) Fibrinolytic abnormalities in two different cutaneous manifestations of venous disease. J Am Acad Dermatol 34:204-8
Spiers, E M; Lazarus, G S; Lyons-Giordano, B (1996) Expression of plasminogen activators in basal cell carcinoma. J Pathol 178:290-6
Walsh, L J (1995) Ultraviolet B irradiation of skin induces mast cell degranulation and release of tumour necrosis factor-alpha. Immunol Cell Biol 73:226-33
Whitaker-Menezes, D; Schechter, N M; Murphy, G F (1995) Serine proteinases are regionally segregated within mast cell granules. Lab Invest 72:34-41
Lyons-Giordano, B; Lazarus, G S (1995) Skin abnormalities in mice transgenic for plasminogen activator inhibitor 1: implications for the regulation of desquamation and follicular neogenesis by plasminogen activator enzymes. Dev Biol 170:289-98

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