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. ? ?
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