Cell movement is an essential component of the inflammatory response. After arrest of circulating leukocytes on the endothelial layer, leukocytes move to the site of extravasation, undergo diapedesis, and finally migrate to sites of infection. In these processes, various types of leukocytes will be recruited and guided by chemotactic gradients mediated by a class of cytokines, the soluble chemokines, or by other molecules bound to the endothelial cell surface. Our overall objective is to investigate how the regulation of cell motility is coordinated with transcription during inflammation. The general hypothesis of this proposal is that the movement of cells participating in the inflammatory response is coupled to the transcription of certain genes that code for various cytokines. This is thought to occur via factors, including intracellular calcium and the Rho family of small GTP-binding proteins, regulating the organization, dynamics and biomechanical properties of cells and, in turn, their motile behavior. A related aspect of this work will address how cell locomotion is linked to gene expression via transcriptional regulation. We will then study the regulation of motile events in the process of leukocyte extravasation through the endothelium. A novel aspect of this proposal is that most of these studies will be conducted on individual cells using imaging and new photomanipulative techniques.
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