Opposing Mechanisms of Stabilizing and Destabilizing Receptors

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DESCRIPTION (provided by applicant): Opposing mechanisms of stabilizing and destabilizing receptors. The control of barrier integrity in the vascular endothelium is central to medicine. In essence the classic signs of inflammation (rubor, calor, dolor, tumor) are products of a destabilized barrier. The main premise of this grant application is that there are competing ligand-receptors that signal through converging pathways that determine the level of stability/instability of the endothelial barrier. Specifically, we will study the stabilizing and destabilizing influences on the endothelial barrier of, respectively, the Robo1 receptor and the receptor for interleukin-1b (IL1R). We hypothesize that the opposing signals from these receptors are due to the activation of opposing GTPase activating proteins (GAP) and guanine nucleotide exchange factors (GEF) that determine, respectively, the inactive and active state of ARF6 and the strength of cell-cell interactions. We suspect that the mechanistic insights derived in our studies will have broad implications to barrier function and cell-cell interactions in many tissues. Our work will suggest for the first time that it may be possible to uncouple the ability o cytokines to disrupt tissue barriers from their stimulation of transcriptional immunomodulatory pathways.