Mechanisms regulating adhesion-induced Weibel-Palade body exocytosis

我实验室的研究项目专注于内皮细胞。内皮细胞排列在血管中，充当守门人，指导哪些分子和细胞可以进入组织。特别是，内皮细胞在直接损伤和慢性疾病期间调节白细胞的运动。 内皮细胞位于快速流动的血液和静止的组织之间。因此，它们对机械力的变化非常敏感。当白细胞与内皮细胞结合时，它们会迅速减速，导致接触点的力发生巨大变化。这种力的变化被内皮细胞感知并转化为生化信号。 这项建议研究了白细胞结合的机械力如何导致内皮细胞的变化，从而导致被称为韦贝尔-帕拉德小体的细胞内存储颗粒的释放。这些颗粒的含量影响血液凝结和水肿，并能放大慢性病中白细胞的募集。 我们将从人的脐静脉中培养细胞，以重建血管，并从健康志愿者那里获取白细胞。我们将把荧光标记的蛋白质输送到内皮细胞中，以便能够追踪活细胞中的韦贝尔-帕拉德小体。然后我们组装一个流室，模拟血液中的情况。利用这个系统，我们将研究在慢性疾病模型中，在白细胞结合过程中实时调节Webel-Palade小体释放的机制。

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.