Role and Utility of Annexins in Endothelium of Solid Tum

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The broad focus of this project is to understand the molecular mechanisms underlying the effects of the tumor microenviroment on endothelial function and the effects of specific tumor-induced endothelial cell proteins on tumor growth, progression and angiogenesis. Such basic information is essential to develop new diagnostic and therapeutic strategies that may prove useful in improving the early detection and treatment of solid t umors. W e w ill focus p rimarily one haracterizing our new tumor-induced, endothelial and caveolar target, an AnnAl related protein, identified through our proteomic analysis of tumor luminal endothelial cell membranes. We will define the specific nature and function of this protein as well as use our panel of specific antibodies to this new target protein to evaluate expression and function in the context of solid tumors and its endothelium. To this end, we will address the following specific aims: 1. To determine the role of the tumor cell and tissue host environment, including specific angiogenic factors, on its expression, translocation, and externalization in caveolae. 2. To investigate the role of its expression by the tumor endothelium on endothelial cell function, solid tumor growth, and angiogenesis. We will use various rat and mouse tumor model systems as well as multiple biochemical and microscopic methodologies to examine in vivo and in cell culture the function of specific expression in caveolae. For instance, the potential anti-tumor effects of naked antibodies blocking possible protein function will be assessed. With this information, we plan to develop the means to improve the detection and staging of solid tumors as well as elaborate novel strategies for more effective and less toxic anti-cancer treatments.