AS斑块铁沉积与槲皮素干预：巨噬细胞Hepcidin自分泌信号调控

项目名称： AS斑块铁沉积与槲皮素干预：巨噬细胞Hepcidin自分泌信号调控

项目编号： No.81472979

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： 姚平

作者单位： 华中科技大学

项目金额： 75万元

中文摘要： 尽管动脉粥样硬化（AS）斑块铁沉积普遍，但铁假说仍备受置疑。本项目拟以新近发现的巨噬细胞Hepcidin自分泌为切入点，结合肝脏Hepcidin调控通路的新近进展，以ApoE-/-高脂AS模型和ox-LDL诱导活化的巨噬细胞为对象，借助基因转染与沉默、通路激动与阻断、转录因子/启动子结合活性分析等方法，对斑块巨噬细胞Hepcidin自分泌及BMPs/SMAD、ERS、TLRs、HIF等潜在通路层层剖析和验证，阐明其病理生理学意义与信号调控通路。在此基础上，选择可天然靶向富集于AS斑块巨噬细胞且具有良好铁螯合和抗AS效应的槲皮素进行干预，分析其对巨噬细胞Hepcidin自分泌的调控及潜在的作用靶点，从全新的角度深入揭示其拮抗AS的分子机制。本项目的实施，不仅有助于进一步阐释AS局灶性铁沉积特征和病理学意义、丰富AS铁假说，还将为AS的营养干预及植物化学物的开发应用提供新的靶点。

中文关键词： 动脉粥样硬化；槲皮素；巨噬细胞；铁调素；信号调控

英文摘要： Iron hypothesis is still highly questioned in spite of common iron deposition in atherosclerosis (AS) plaque. Based on the new finding of hepcidin autocrine from macrophages, our project is designed to explore systematically the pathophysiological significance for AS progression and potential signaling pathways of hepcidin autocrine following a deep characteristic analysis on iron deposition in the presence of AS, limited research on autocrine signaling pathway of macrophages induced by bacterial infection but emerging studies and recent development on the regulatory pathways implicated in hepatic hepcidin expression. The potential signaling pathways, including BMPs/SMAD, endoplasmic reticulum stress, toll-like receptors, hypoxia inducible factor, and etc will be studied and verified in vivo and in vitro by using (local) gene transfection or silence, signaling activation or inhibition, double fluorescent staining for cellular compartmentalization through laser scanning co-focal technique, chromatinImmunoprecipitation, electrophoretic mobility shift assay and so on. In addition, naturally occurring quercetin is selected for AS intervention due to its target accumulation into plaque macrophages, beneficial iron-chelating and anti-AS activities. The effect and potential target of quercetin on hepcidin autocrine from plaque macrophages will be discussed to elucidate the molecular mechanisms of quercetin against AS from a new perspective. Thus, the project will not only help to further clarify the underlying reason and pathological consequence of focal iron deposition in the presence of AS and enrich iron hypothesis, will also provide a new target for the development and application of phytochemicals and nutritional intervention for AS.

英文关键词： atherosclerosis;quercetin;macrophages;hepcidin;signaling regulation