Regulation of vascular remodeling & angiogenesis by Nogo

血管重塑的调节

• 批准号: 7103599
• 负责人: William C Sessa
• 金额: $ 39.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103599
• 关键词: CHO cells; SDS polyacrylamide gel electrophoresis; angiogenesis; artery; biological signal transduction; cell migration; enzyme linked immunosorbent assay; immunocytochemistry; laboratory mouse; membrane proteins; molecular cloning; nerve /myelin protein; polymerase chain reaction; protein binding; protein isoforms; protein structure function; proteomics; receptor binding; receptor expression; regeneration; terminal nick end labeling; vascular endothelium; western blottings

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.

描述（由申请人提供）：使用蛋白质组学作为发现的诱导方法，我们的实验室在体外和体内鉴定了血管细胞中的蛋白质Nogo-B。这种Nogo同工型的功能作用及其作用机理尚不清楚。在初步数据中，我们表明，与NoGo-A不同的NoGo-B氨基末端促进了内皮和平滑肌细胞的粘附，并用作内皮细胞的化学吸引剂，而拮抗PDGF诱导的平滑肌细胞迁移。此外，在血管损伤的范式中，Nogo-A/B的丧失导致夸张的炎症反应和Nogo-B的新内膜增殖和治疗基因转移，从而挽救了这些敲除表型。此外，我们还将AM Nogo-B的新型受体克隆在血管细胞中。因此，我们假设Nogo-B与其同源受体结合是一种新型的内源性调节系统，可协调对血管损伤或组织缺血的血管反应。我们建议：1。定义Nogo-B在动脉生成和血管生成过程中的作用； 2。表征血管细胞中Nogo-B的受体，并3.阐明Nogo-B氨基末端如何调节内皮细胞功能的机制。总的来说，这些实验将唯一地定义了Nogo在血管中的作用，这可能导致控制血管生成，动脉生成和血管重塑的潜在疗法。