Leukocyte Mechanotransduction of Fluid Shear Stress

描述(申请人提供)：本方案的主题是流体剪切力介导的白细胞激活的调节，这是循环中急性炎症的第一步。这项拟议的研究将集中在白细胞机械转导的早期事件，并研究细胞感知局部流体切应力(由于粘性血流)并将其转化为生物反应(即伪足回缩和细胞失活)的机制。我建议检验关于细胞膜是细胞的机械转导中心的假设。为此，我将研究这一机制的三个关键组成部分：1)跨膜蛋白受体，如CD18整合素，作为机械换能器，在切应力暴露时表现出不同的活性；2)机械换能器的表面水平调节白细胞对剪切力的反应；以及3)细胞膜(悬浮介质)的物理化学性质。这些蛋白质)通过调节这些剪应力传感器的激活和水平来调节白细胞的剪切反应。这些研究将阐明一种可能的控制机制，在没有激动剂的情况下，防止生理条件下白细胞伪足的形成和迁移。

DESCRIPTION (provided by applicant): The subject of this proposal is fluid shear stress-mediated regulation of leukocyte activation, one-of the first steps in acute inflammation in the circulation. The proposed research will focus on early events in leukocyte mechanotransduction and examine the mechanism by which cells sense and converts local fluid shear stresses (due to viscous blood flow) into a biological response (i.e., pseudopod retraction and cell deactivation). I propose to examine the hypothesis that the cell membrane is a mechanotransduction center for the cell. For this purpose, I will investigate three key components of this proposed mechanism: 1) transmembrane protein receptors, such as CD18 integrins, act as mechanotransducers that exhibit altered activity upon shear stress exposure; 2) surface levels of mechanotransducers regulate leukocyte responses to shear stress; and 3) the physicochemical properties of the cell membrane (the suspending medium for. these proteins) modulate the leukocyte shear response by regulating the activation and levels of these shear stress transducers. These studies will elucidate a possible control mechanism which, in the absence of ' agonists, prevents leukocyte pseudopod formation and migration under physiological conditions.