Mechanisms regulating adhesion-induced Weibel-Palade body exocytosis

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The research program in my laboratory focuses on endothelial cells. Endothelial cells line the blood vessels and serve as gatekeepers, directing what molecules and cells can pass through into the tissue. In particular, endothelial cells regulate the movement of white blood cells during both immediate injury and during chronic disease. Endothelial cells are positioned between the fast flowing blood and the stationary tissue. As a result, they are very sensitive to changes in mechanical force. When white blood cells bind to endothelial cells, they rapidly decelerate, resulting in a large change in force at the point of contact. This change in force is sensed by the endothelial cells and translated into biochemical signals. This proposal examines how the mechanical force of white blood cell binding leads to changes in the endothelial cells that results in the release of intracellular storage granules called Weibel-Palade bodies. The contents of these granules affect blood clotting and edema, and can amplify the recruitment of white blood cells in chronic disease. We will culture cells from human umbilical veins to recreate blood vessels and obtain white blood cells from healthy volunteers. We will deliver fluorescently labeled proteins into the endothelial cells to enable tracking of Weibel-Palade bodies in living cells. We then assemble a flow chamber that mimics the conditions found in the blood stream. Using this system we will examine mechanisms that regulate the release of Weibel-Palade bodies in real-time during white blood cell binding in a model of chronic disease.