The equilibrium between stability and regeneration is critical to maintaining a functional vasculature. In the mature circulatory system, the endothelium provides critical barrier and regulatory functions by controlling fluid, nutrient and cellular transport between intravascular and extravascular compartments. Vascular injury induces an inflammatory response that stimulates the release of cytokines and growth factors. These factors weaken endothelial cell-cell junctions, stimulate migration and proliferation, and pave the way for remodeling and regeneration. Thus, there is constant tug-of-war within the vascular endothelium between signals that maintain vascular homeostasis/stability and signals that incite regeneration/instability. The central hypothesis for this competitive renewal is that Slit-Robo4 is an endogenous ligand receptor pathway that drives the balance toward homeostasis/stability. If this model is correct, then Robo4 signal might oppose the destabilizing influences of injury, ischemia, and inflammation mediated by a variety of angiogenic and inflammatory cytokines.
Specific Aim 1 : Elucidate the mechanism of Robo4 signaling.
Specific Aim 2 : Determine whether Slit-Robo4 is a broad platform for blunting the vascular response to cytokines. At the conclusion of our studies, we hope our contribution will be to demonstrate that Robo4 is a broad vascular stabilization program and to define its downstream signaling cascade.
At the conclusion of our studies, we hope our contribution will be to demonstrate that Robo4 is a broad vascular stabilization program and to define its downstream signaling cascade. In pursuing these objectives we hope to demonstrate that activating this vascular stability program will reduce pathologic endothelial hyperpermeability in a variety of ischemic and inflammatory diseases.
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