Regulation of vascular remodeling & angiogenesis by Nogo

描述(申请人提供)：使用蛋白质组学作为一种诱导发现的方法，我们的实验室已经在体外和体内鉴定了血管细胞中的Nogo-B蛋白。这种Nogo异构体的功能作用和作用机制尚不清楚。在初步数据中，我们发现Nogo-B的氨基末端与Nogo-A不同，它促进内皮细胞和平滑肌细胞的黏附，并在拮抗PDGF诱导的平滑肌细胞迁移的同时，作为内皮细胞的趋化因子。此外，在血管损伤的范例中，Nogo-A/B的缺失导致了过度的炎症反应和新生内膜的增殖，Nogo-B的治疗性基因转移挽救了这些基因敲除的表型。此外，我们还克隆了一种新的AM Nogo-B受体，该受体在血管细胞中表达。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，协调血管损伤或组织缺血的血管反应。我们建议：1.明确Nogo-B在动脉形成和血管生成中的作用；2.鉴定血管细胞中Nogo-B的受体；3.阐明Nogo-B氨基末端如何调控内皮细胞功能的机制。总的来说，这些实验将独特地定义Nogo在血管系统中的作用，这可能导致管理血管生成、动脉生成和血管重塑的潜在疗法。

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.