BASEMENT MEMBRANE ZONE MOLECULAR AND CELL BIOLOGY IN EB

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The proposed program project will study various aspects of the molecular and cellular biology of various basement membrane zones of the skin, including the epidermal-dermal interface and the vascular basement membrane zone. The goals of this project focus on characterizing expression and regulation of basement membrane zone proteins of importance in pathophysiologic events involved in both normal physiology and epidermolysis bullosa (EB). We shall attempt to define structures and proteins involved in the functional integrity of the basement membrane zone and to characterize mechanisms governing their synthesis, secretion and degradation. The specific projects are as follows. I. "Candidate Protein Clones in EB" will develop and use probes to map genes and establish polymorphisms in hereditary EB and define possible relationships between acquired EB and HLA. II. "Keratinocyte Locomotion and Protease Expression" will examine the attachment and migratory behavior of keratinocytes and characterize the repertoire of metalloproteases expressed by the migrating cells. III. "Metabolism of the Dermal Microvascular Basement Membrane" will examine matrix protein synthesis by normal and activated endothelial cells and compare the behavior of these cells with that of endothelial cells from patients with EB. IV. "Regulation of Expression of Extracellular Matrix Molecules and Degradative Enzymes in Normal and RDEB Fibroblasts in Monolayer Culture and in a Reconstituted Skin Model" is predicated on the notion that excessive proteolysis is fundamental to understanding the connective tissue destruction that characterizes RDEB. It will explore the mechanisms of regulation of metalloprotease expression in a 3-dimensional model of reconstituted skin. V. "Biology of the Interaction of Keratinocytes with Basement Membranes" will determine what role moesin, a heparin-binding receptor protein, may play in processes of cell-cell and cell-matrix interactions in cell spreading, growth and motility of the epidermis during development and wound healing in both normal and EB- derived cells. Ultimately, we hope that these studies will lead to better understanding of the function of the basement membrane zone and to more effective therapeutic approaches to EB.