Many of the disease processes which affect skin have a prominent vascular component. This is especially true of acute and chronic inflammatory diseases of both immune and nonimmune etiologies. Recent in vitro studies have established the importance of endothelial activation in inflammatory processes in which endothelial- leukocyte interactions are a prominent feature. A critical event in this activation response is the rapid and specific induction of expression of endothelial-leukocyte adhesion molecules such as E-Selectin. In this project, we propose to evaluate the feasibility of combining genetic manipulation of murine embryonic stem cells with blastocyst-mediated chimera formation as a novel model for investigating vascular biologic features of skin disease. In support of this overall goal we will pursue the following Specific Aims: 1. Generation of E-Selectin/Chimeric mice for analysis of dermal vasculature; 2. Determination of lymphocyte homing in models of endothelial activation; 3. Application of E-Selectin/Chimeric mice to basic studies of skin pathophysiology. If successful, these studies are expected to provide fundamentally new insights into the cutaneous biology and pathophysiology of the dermal microvasculature.
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