Regulation of vascular remodeling & angiogenesis by Nogo

描述（由申请人提供）：本实验室利用蛋白质组学作为诱导发现的方法，在体外和体内血管细胞中鉴定出Nogo-B蛋白。Nogo异构体的功能作用及其作用机制尚不清楚。在初步数据中，我们发现Nogo-B的氨基末端，与Nogo-A不同，促进内皮细胞和平滑肌细胞的粘附，并作为内皮细胞的化学引诱剂，同时拮抗pdgf诱导的平滑肌细胞迁移。此外，在血管损伤的范例中，Nogo-A/B的缺失会导致过度的炎症反应和新生内膜增殖，而Nogo-B的治疗性基因转移可以挽救这些基因敲除表型。此外，我们还克隆了一种在血管细胞中表达的Am Nogo-B的新受体。因此，我们假设Nogo-B与其同源受体结合是一种新的内源性调节系统，可协调血管损伤或组织缺血时的血管反应。我们建议：1。明确Nogo-B在动脉生成和血管生成中的作用；2. 描述Nogo-B在血管细胞中的受体。阐明Nogo-B的氨基端调控内皮细胞功能的机制。总的来说，这些实验将独特地确定Nogo在血管系统中的作用，这可能会导致潜在的治疗方法来控制血管生成、动脉生成和血管重塑。

DESCRIPTION (provided by applicant): 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.