Endothelial Cell Flow Response: Local or Integrated?

描述(申请人提供)：血管内皮细胞对循环系统复杂的血液动力学环境的反应对心血管系统的病理生理调节至关重要；然而，这种信号转导的机制仍然知之甚少。最近的体内证据表明，细胞能够对局部剪切力做出反应，单细胞内极化的磷酸酪氨酸蛋白的表达证明了这一点。该项目的目标是在体外系统中表征内皮细胞对剪应力梯度的反应，在该系统中，流变条件可以被控制和很好地定义。在这样做的过程中，该项目将解决两个关键问题：内皮细胞能否通过局部信号对剪切力做出反应，以及内皮细胞剪切力反应是否需要细胞-细胞接触？目标1将研究明确定义的血流中的局部内皮细胞结构和信号。目的2将研究内皮细胞-细胞接触在将流体切应力信号传递到细胞中的作用。总而言之，这些目标将定义细胞能够对局部剪应力做出反应的机制。这项研究旨在弥合体内和体外内皮细胞对血流反应的观察之间的差距。

DESCRIPTION (provided by applicant): Endothelial cell response to the complex hemodynamic environment of the circulatory system is critical to the pathophysiological regulation of the cardiovascular system; however the mechanism by which this signal is transduced remains poorly understood. Recent in vivo evidence suggests that cells are capable of responding locally to shear stress evidenced by polarized phosphotyrosine protein expression within single cells. The goal of this proposed project is to characterize endothelial cell response to shear stress gradients in an in vitro system where the rheological conditions can be controlled and well-defined. In doing so, this project will address two key questions: can endothelial cells respond to shear stress through localized signaling, and is cell-cell contact necessary for endothelial cell shear stress response? Aim 1 will be to investigate localized endothelial cell structure and signaling in well-defined flows. Aim 2 will be to investigate the role of endothelial cell-cell contact in transducing fluid shear stress signals to the cell. Together, these aims will define the mechanisms by which cells are capable of responding locally to shear stress. This study is intended to bridge the gap between in vivo and in vitro observations of endothelial response to flow.