Metrnl作为心脑血管疾病防治新靶标的研究

We have recently identified a novel adipokine Metrnl, and demonstrated this secreted protein is an inherent insulin sensitizer. In the last three years for exploring the new function of this novel protein, we have shown that Metrnl is highly expressed in and secreted from vascular endothelial cells. Using Metrnl conditional knockout mice, we create a strain of Metrnl whole-body knockout mice and various strains of mice with different cell-specific knockout of Metrnl, such as endothelial cell-specific knockout, adipocyte-specific knockout, intestinal epithelial cell-specific knockout, and hepatocyte-specific knockout. Among these various strains of cell-specific knockout mice, only endothelial cell-specific Metrnl knockout mice display a significant reduction of serum Metrnl levels, revealing that endothelium-derived Metrnl is the only major source of circulating Metrnl found by now. Endothelial cell-specific knockout of Metrnl causes endothelial dysfunction. Preliminary observations show that Metrnl deficiency is associated with atherosclerosis in the mouse and human. Also, Metrnl may play a role in ischemic stroke and endotoxic shock. This project will further study the importance and molecular mechanism of Metrnl in the abovementioned cardio-cerebro-vascular disease, using various strains of Metrnl knockout mice including double genes knockout of Metrnl and ApoE. We will also test the therapeutic value of humanized recombinant protein and gene therapy of Metrnl, to further verify its potential as a therapeutic target for the disease. Based on understanding the potential role of Metrnl as a ligand for receptor or as an enzyme for biochemical pathway, as well as the potential domain for Metrnl function, we will screen the Metrnl mimics, including modified proteins, small peptides and small-molecule chemicals, which need to be verified similar to Metrnl in the function and mechanism. Our long-term goal is to use Metrnl protein and its related molecules for prevention and treatment of major cardio-cerebro-vascular disease.

我们最近首次报道了全新脂肪因子Metrnl，揭示了该分泌蛋白是机体内在的胰岛素增敏剂。在近三年针对该新蛋白的新功能探索中，本项目观察到Metrnl在血管内皮细胞高表达、可分泌；进而，利用本室独有的Metrnl条件性基因敲除小鼠，构建了全身性及各种细胞特异性敲除小鼠，发现内皮Metrnl是迄今检测到的血液Metrnl的唯一主要来源，Metrnl缺乏可引起内皮功能受损，与动脉粥样硬化有关；同时，发现Metrnl在缺血性脑卒中、内毒素休克中的表达改变及功能表型。进一步，将采用Metrnl和ApoE双基因敲除小鼠等多种模式动物，明确Metrnl在心脑血管疾病中的重要性及分子机制，并采用人源化重组蛋白等多种生物制品，系统性确证Metrnl作为疾病防治的新靶标。最后，在阐释Metrnl生物学本质和功能结构域基础上，筛选和确认Metrnl功能拟似物。本项目为利用新功能蛋白来防治重大心脑血管疾病奠定基础。

分泌蛋白可调控代谢、免疫、心脑血管等多个系统，在健康、疾病、衰老过程中发挥重要作用，可作为疾病防治的药物、靶标、生物标志物。我们前期首次确认了全新脂肪因子Metrnl并命名为Subfatin，揭示了该分泌蛋白是机体内在的胰岛素增敏剂。本项目成功培育了新型分泌蛋白Metrnl新的基因工程动物模型多种，首次阐明了血管内皮细胞是血液循环Metrnl的主要来源，该分泌蛋白通过经典的内质网-高尔基体途径释放入血，明确了Metrnl在线粒体等亚细胞定位；发现心肌梗死、缺血性脑卒中患者的血液Metrnl水平下降，与动脉粥样硬化内皮损伤有关，Metrnl缺乏促进动脉粥样硬化发生发展，内皮细胞Metrnl起到关键作用；揭示了Metrnl缺乏促进动脉粥样硬化的机制与内皮细胞功能障碍有关，涉及eNOS的Ser1177位点磷酸化下降导致内皮依赖性血管舒张反应受损，以及NFkB通路增强引起内皮炎症反应激活；探索了人Metrnl重组蛋白或基因可挽救血管内皮功能障碍、促进血管新生修复、减轻内毒素损伤，显示了Metrnl对心脑血管疾病的治疗学意义；研究了Metrnl配体受体机制及功能结构域。从而，为发展心脑血管疾病新的干预靶标和新的防治措施奠定基础。.发表论文26篇，其中SCI论文17篇，影响因子5以上15篇、10以上3篇，入选ESI全球高被引用论文1篇；主编专著1部；国内外发明专利授权9项、申请全球PCT专利等7项；培养研究生31名(毕业17名)；国际国内邀请报告38次，主办大型会议6次；获上海市科技进步一等奖、国庆70周年纪念章；当选为中国药理学会副理事长、心血管药理主任委员，上海市药理学会理事长，亚洲血管生物学协会常务理事；受聘为4种SCI期刊编委；入选斯坦福大学(Stanford University)和爱思维尔集团(Elsevier Science)发布的世界位居前2%的科学家(World’s Top 2% Scientist)中的“终身科学影响力(1960-2019)”榜单。