This application for a Mentored Research Scientist Development Award is designed to provide the candidate with the opportunity to develop an independent area of research focusing on the molecular and cellular biology of dermal microvascular endothelial intercellular junctions. The research will be carried out at Northwestern University Medical School where the faculty have recognized expertise in the areas of intercellular junction assembly, endothelial cell biology, and dermatology. The formation of adhesive intercellular junctions by vascular endothelium is thought to be critical in the regulation of fluid balance between the plasma and tissue compartments. The loss of this barrier function of endothelial cells is a prevalent feature in numerous pathologies that involve inflammation and edema, and in the skin, this psoriasis and dermatitis. In addition, endothelial intercellular junctions may be regulated during angiogenesis and may provide control over endothelial cell migration into a wound area. Two types of approaches will be taken to investigate endothelial junction assembly. First, specific components of the junctions will be expressed in fibroblasts to reconstitute complexes that may form between proteins during junction assembly. This approach will allow for the identification of protein-protein interactions that can be further investigated using purified proteins in vitro. Secondly, mutants of the endothelial junction proteins will be expressed in endothelial cells to specifically inhibit the function of the endogenous protein and identify the role of each protein in junction assembly. By analyzing mutants that inhibit endothelial junction assembly, the impact of improper junction formation on endothelial cell function will be determined. Emphasis will be placed on understanding how endothelial junctions influence the ability of endothelial cells to function as a barrier to fluid and solutes and how endothelial junctions may regulate migration. It is anticipated that the results of this study will provide fundamental information regarding the altered behavior of endothelial cells in various cutaneous disorders that involve inflammation, edema, or angiogenesis.
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