The overall goal of the current application is to understand the mechanisms by which expression of annexin II may be controlled in specific settings of cellular differentiation and development. Our published studies have revealed a role for annexin II in promoting assembly of plasminogen and tissue plasminogen activator, and subsequent plasmin generation on the surface of endothelial cells, macrophages, and myeloid cells. New preliminary data suggest that the expression of annexin II may be developmentally regulated in both the chick an"""""""" mouse embryo. While annexin II is expressed in the developing brain and spinal cord, this expression is lost in the adult organism. Similarly, expression of annexin II is strongly upregulated in neuronal cells in vitro by the neurotrophin, nerve growth factor (NGF). At the same time, annexin II is expressed in the embryonic heart, but not in the postnatal heart. Similarly, expression of annexin II in endothelial cells is upregulated by the angiogenic factor, hepatocyte growth factor. These new findings suggest that the function of annexin II may extend beyond the maintenance of blood fluidity. We hypothesize that annexin II promotes normal neuronal an"""""""" cardiovascular differentiation in the developing vertebrate embryo by fostering cell surface proteolytic activity an"""""""" promoting tissue remodeling. To investigate this hypothesis, we plan [1] to determine the pattern of annexin II expression an"""""""" the consequences of its disruption during organogenesis in the developing chick embryo, [2] to identify the temporal an"""""""" spatial settings in which the annexin II promoter is active during development, [3] to delineate the mechanism by which NGF stimulates annexin II protein an"""""""" mRNA expression, and [4] to define the role of annexin II in blood vessel development in response to angiogenic growth factors.
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