免疫干预转变巨噬细胞脂质处理模式及其生存命运抑制动脉粥样硬化研究

项目名称： 免疫干预转变巨噬细胞脂质处理模式及其生存命运抑制动脉粥样硬化研究

项目编号： No.81470483

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 魏宇淼

作者单位： 华中科技大学

项目金额： 73万元

中文摘要： 巨噬细胞通过模式识别受体吞噬氧化脂质，启动维持炎症反应并最终凋亡坏死是动脉粥样硬化发展的基本脉络。如能利用特异性抗体分子作为介导，免疫干预转变这一通路，使巨噬细胞对脂质的模式识别受体非特异性吞噬-诱导炎症反应处理模式转变为特异性受体吞噬-胆固醇外流转运模式，可抑制炎症反应形成，促进斑块内胆固醇外流，避免脂质过度负荷，减轻巨噬细胞死亡命运，实现动脉粥样硬化的抑制。具体内容包括：制备负载MDA-apoB-PF抗体的apoE敲除鼠模型，观察血管组织巨噬细胞氧化脂质吞噬和代谢途径的改变，NF-κB炎症系统的抑制，PPARα及胆固醇外流分子表达的增强；观察负脂巨噬细胞自噬、凋亡的命运差异和动脉粥样硬化病变的形成情况。同时，从离体细胞水平探讨上述作用及其机制，并用多层次药物干预作为验证。最终明确MDA-apoB-PF抗体介导巨噬细胞脂质处理模式和巨噬细胞生存命运的转变对动脉粥样硬化的防治作用。

中文关键词： 动脉粥样硬化；免疫干预；巨噬细胞；脂质；生存命运

英文摘要： The general process of pathogenesis of atherosclerosis involved macrophage is initiated by the phagocytosis of oxidized lipid via pattern-recognition receptors, which can induce and maintain the inflammatory response and, ultimately, the macrophage will die through apoptotic or necrotic mechanism after lipid overloaded. One strategy to prevent the pathogenesis of atherosclerosis is to transform the macrophage phagocytosis pattern to the oxidized lipid and promote to efflux the cholesterol from atherosclerosis plaque. We hypothesize that using the specific antibody against oxidized lipid will induce the macrophage in dealing with lipid from phagocytosis via pattern recognition receptors-inducing inflammation to phagocytosis via specific antibody-promoting cholesterol efflux. This pathway of lipid-processing pattern will inhibit inflammation reaction, promote cholesterol efflux, avoid excessive lipid load, and improve macrophage survival fate, which all contribute to the pathogenesis of atherosclerosis. The main parts in the present project include: the intervention with anti-MDA-apoB-PF antibody in apoE-/- mouse model, the observation of cholesterol phagocytosis and metabolic changes in animal tissue; the observation of the inhibition of NF-κB regulated inflammation reaction; the observation of the expression PPARα and cholesterol efflux related molecules; the observation of the fate of macrophage overloaded lipid, including autophagy, apoptosis, and necrosis, and at last we will observe the difference of atherosclerosis lesions in different treatment groups. Meanwhile, we will investigate the mechanisms in macrophage cells in vitro. The main purpose is to elucidate the role and mechanism of antibody against MDA-apoB-PF which mediates the transforming of lipd-processing pathway and improving the survival fate of macrophage in the prevention and treatment of atherosclerosis.

英文关键词： atherosclerosis;immunological intervention;macrophages;lipid;survival fate