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.
Opposing mechanisms of stabilizing and destabilizing receptors. In any inflammatory condition from arthritis to eye disease a central issue is the integrity of the blood vessel walls. Inflammatory cytokines or proteins compromise the vessel wall allowing fluid and cells traveling within the blood vessel to seep into tissues. We will understand how these cytokines disrupt the vascular barrier and initiate tissue swelling and destruction, and how other proteins seek to stabilize the vascular wall. Our studies have a direct application to medicine as it reveals a new pathway that if blocked by a pharmaceutical will reduce tissue disruption and destruction in animal models of inflammation and arthritis.
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