The role of cadherins, a multigene family of calcium dependent cell adhesion molecules, in regulating the growth, development and repair of the vasculature in skin is not well-defined. Three well characterized cadherins, E-(epithelial), N-(neural), and P-(placenta) cadherin have been shown to promote maintenance of cell junctions in established tissues as well as cell sorting during embryogenesis. As most of the cadherin family members share a conserved cytoplasmic domain, we designed a degenerate PCR cloning approach to isolate additional members of the family. Using this method, a novel member of the cadherin gene superfamily, cadherin 5, was cloned and characterized. Using in situ hybridization and immunostaining with cadherin 5 specific reagents, we found that cadherin 5 plays an integral role in the formation and maintenance of endothelial structures. We postulate that cadherin 5 function is regulated by its interaction with cytoplasmic binding proteins called catenins. Based on our preliminary data, we predict that when inflammatory cells migrate through existing vascular structures, the cadherin/catenin interaction is modified by a signal transduction event, causing loss of cadherin/catenin binding and leading to the opening of endothelial junctions. This hypothesis will be tested in Aim 1 by characterizing the subcellular distribution of cadherin 5, the catenins and defined junctional proteins in an in vitro neutrophil transmigration assay using laser scanning confocal microscopy.
Aims 2 and 3 will address the mechanism(s) by which cadherin 5 subcellular localization changes occur during junction opening and reformation.
In Aim 4, the role of phosphorylation in modifying the interaction between cadherin 5 and its binding proteins during endothelial junctional events will be studied. The proposed studies will lay the groundwork for studying the cadherin signal transduction pathway in endothelial cells. In addition, they will provide insight into the regulation of endothelial junctional events during angiogenesis and inflammation. As many cutaneous diseases of the skin involve the infiltration of immune cells, the data generated in this proposal will be useful in defining the role of the endothelium in these diseases.
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