RENAL MICROVASCULAR ENDOTHELIAL CELL DIFFERENTIATION

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Description: (Abstract of the project) The development, maintenance and reestablishment of renal glomerular and tubular structure and function are areas of intense interest and investigation. Reversible renal glomerular and tubular dysfunctions are noted in a variety of disease states. Advances in our understanding of renal function in the last five years have mainly been in the areas of epithelial cell-cell, cell-matrix and cell-growth factor interactions and in the development of adherens and tight junctional complexes. While the development, maintenance and regulation of endothelial barrier function has been well-studied functionally, the relative flatness of the endothelial cell compared to most epithelial cells studied has resulted in slower progress in morphological-based investigations. Endothelial cell adherens junctions contain an endothelial specific cadherin - VE-cadherin which complexes to (alpha- and beta-catenin, plakoglobin and p120cas and recent studies have found that endothelial permeability is modulated by regulation of the adherens junctions. Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1 /CD31), an Ig family member expressed on endothelia from the hemangioblast stage through adulthood, is located at lateral borders of endothelial cells and is thought to play a role in the early stages of vascular genesis and angiogenesis. In this proposal we will examine the role of PECAM-1 as a beta-catenin binding moiety and as a scaffolding upon which beta-catenin phosphorylation is regulated, thus regulating beta-catenin's participation in adherens junction formation and gene expression. The hypothesis to be tested is that PECAM-1 is essential for the formation, maintenance and dynamic modulation of renal endothelial cell junctions. Signaling pathways involving dynamic selective PECAM-1 tyrosine and serine/threonine phosphorylation/ dephosphorylation in vascular endothelial cells will be elucidated using a variety of methods to determine the roles of PECAM-1 in the development and maintenance of endothelial differentiation and polarity and during responses to hypoxic injury.