Using proteomics as an inductive approach for discovery, our lab has identified the protein Nogo-B in vascular cells in vitro and in vivo. The functional role of this Nogo isoform and its mechanism of action are unknown. In preliminary data, we show that the amino terminus of Nogo-B, unlike Nogo-A, promotes the adhesion of endothelial and smooth muscle cells, and serves as a chemoattractant for endothelial cells while antagonizing PDGF-induced smooth muscle cell migration. Moreover, in a paradigm of vascular injury, the loss of Nogo-A/B results in an exaggerated inflammatory response and neointimal proliferation and therapeutic gene transfer of Nogo-B rescues these knockout phenotypes. In addition, we have cloned a novel receptor for Am Nogo-B that is expressed in vascular cells. Thus, we hypothesize that Nogo-B binding to its cognate receptor is a novel endogenous regulatory system that coordinates the vascular response to vascular injury or tissue ischemia. We propose to: 1. Define the role of Nogo-B during arteriogenesis and angiogenesis;2. Characterize the receptor for Nogo-B in vascular cells and 3.Elucidate the mechanisms of how the amino terminus of Nogo-B regulates endothelial cell functions. Collectively, these experiments will uniquely define the role of Nogo in the vasculature that may lead to potential therapies that govern angiogenesis, arteriogenesis and vascular remodeling.
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