铁稳态代谢感应新基因功能及分子机制研究

Iron homeostasis is essential for maintaining human health. Identification of novel iron modifiers and their functional studies has led to big breakthroughs in the field. Previously, we discovered several novel genes, such as Mon1a and Sidt1, which are closed related to iron metabolism (Nature Genetics 2005，Nature Genetics 2007; Nature 2008; Human Molecular Genetics 2012, and Nature Communications 2014). The molecular mechanisms of how Mon1a and Sidt1 modulates iron homeostasis remains to be defined. Therefore, we constructed the Mon1a and Sidt1 gene knockout mice. Preliminary phenotypic studies revealed that Mon1a knockout mice displayed significantly changes in macrophage iron recycling, while Sidt1 knockout mice presented drastically decreased liver iron. These phenotypic characteristics of Mon1a and Sidt1 knockout mice provide reliable genetic evidence for supporting our hypothesis, which is that the gene Mon1a and Sidt1 play roles in iron metabolism. By applying cutting-edge biomedical technologies in those established Mon1a and Sidt1 conditional gene knockout mice, this proposal aims to systematically study underlying molecular mechanisms of how Mon1a and Sidt1 functions as iron modifiers in sensing and responding to deregulated iron homeostasis. The findings may pave ways for further understanding molecular regulatory networks of iron homeostasis and its potential therapeutic implications in iron related diseases.

铁稳态代谢对维持机体健康至关重要。铁修饰基因发现成为阐明铁代谢调控理论突破口和攻关焦点。近期我们发现多个铁代谢基因，成果先后发表在Nature Genetics（2005，2007）、Nature（2008）、Human Molecular Genetics（2012）、Nature Communications（2014）等期刊，其中新的铁修饰基因Mon1a和Sidt1是否或如何参与铁稳态调控是关键问题。我们通过构建和分析基因敲除小鼠，发现Mon1a敲除改变巨噬细胞铁再循环；Sidt1敲除造成肝脏铁下降等特异表型，初步数据提供了新基因Mon1a和Sidt1参与铁稳态代谢调控的可靠依据。本项目拟以Mon1a和Sidt1组织特异敲除小鼠为主要实验模型，深入阐明新基因调控感应铁稳态的靶点器官，系统回答新基因功能及分子调控机制，为丰富完善铁稳态代谢理论及铁代谢相关疾病的防治提供重要理论依据。

在项目资助下，围绕铁稳态和铁死亡新基因新机制获得系列重要成果，合计在Blood、Hepatology、Circulation Research、PNAS、Signal Transduction and Targeted Therapy和Advanced Science等国际著名期刊发表研究论文50篇，其中综述7篇。主要研究成果概述如下：(1）在肝脏损伤与铁过载/铁死亡领域，发现转运蛋白SLC7A11通过感应体内铁状态调控细胞铁死亡的重要功能和机制（Hepatology 2017，共同通讯作者，封面论文，高被引论文）；发现转铁蛋白通过调控铁死亡抑制肝脏纤维化发生的生理效应及分子机制，并揭示SLC39A14通过转运非转铁蛋白结合铁而诱发肝细胞发生铁死亡并进而导致肝脏纤维化的分子机制。该研究发现转铁蛋白、SLC39A14及铁死亡是肝脏纤维化防治的重要新靶点（Blood，2020，共同通讯作者，封面论文，杂志专家评论）；发现抑制硫氧还蛋白还原酶TXNRD可诱发脂质过氧化及铁死亡发生，揭示TXNRD是铁死亡的关键调节因子；建立全球首个药物诱导肝脏铁死亡损伤小鼠模型（Signal Transduction and Targeted Therapy，2020，共同通讯作者）。(2)在心脏疾病与铁过载/铁死亡领域：在国际上首次揭示铁离子失衡诱发铁死亡是心肌细胞损伤的重要机制与防治靶点，并阐明铁代谢基因Ferritin、Hmox1及SLC7A11是调控心肌细胞铁死亡发生的关键基因（PNAS, 2019，共同通讯作者，高被引论文，热点论文； Circulation Research，2020，共同通讯作者）。（3）利用基因敲除小鼠模型，进一步阐明转铁蛋白受体（TFR）及HJV等基因在造血系统、肌肉或脂肪中发挥维持器官稳态的重要功能及分子机制（Haematologica 2019； Journal of Cachexia, Sarcopenia and Muscle 2019；Advanced Science 2020）。.承办2次国际学术大会。培养硕士研究生20人，博士研究生19人，博士后10人。