肌肉铁稳态代谢的生理及分子机制

Iron homeostasis is essential for maintenance of normal metabolism and health. Our previous discoveries have set up a solid platform for better understanding the molecular mechanisms of iron homeostasis in macrophages (Nature Genetics 2007; Blood 2011; Haematologica 2012) and hepatocytes (Nature 2008; Hepatology 2012). In this proposal, we focus on functional characterization of how iron hemostasis is achieved in muscle, which has been well-known as the largest energy consuming organ and demanding large amount of iron for fulfilling its proper functions, including newly identified endocrine functions. Specifically, we will take advantage of our established multiple genetic model systems in conjunction with tissue specific Cre/loxP systems to dissect the physiological roles and its molecular mechanisms of iron uptake, storage and export in three types of muscles, namely cardiomyocyte, skeletal muscle and smooth muscle, by genetic deletion of three major iron related genes, including TfR1 (Transferrin receptor 1), Fpn1 (Ferroportin) and Ferritin H (Iron storage protein). In addition, we aim to study how dysregulation of iron homeostasis affecting the endocrine functions in muscle. Our preliminary observation supports TfR1 as the essential iron importer in cardiomyocyte and it may play vital roles in maintenance of proper heart function in mice. Taken together, the findings stemming from this project could make significant contributions in elucidating the physiological functions of iron hemostasis and its molecular networks in muscle. As the result, this proposal possesses potential therapeutic applications for treatment of many muscle-related diseases.

铁稳态对维持新陈代谢及机体健康至关重要。我们前期在巨噬细胞（Nature Genetics 2007; Blood 2011; Haematologica 2012）及肝细胞（Nature 2008; Hepatology 2012）铁稳态代谢分子机制方面有系列重大发现。肌肉组织是能量代谢以及铁离子需求最为活跃的器官之一，并具有重要的内分泌功能，但人们对其铁代谢机制知之甚少。本项目通过Cre/loxp技术制备TfR1（转铁蛋白受体）、Fpn1（泵铁蛋白）及Ferritin H（铁蛋白重链）心肌、骨骼肌或平滑肌的基因敲除小鼠模型，深入系统的研究肌细胞铁离子摄入、泵出及储存的机制，并进一步探讨铁稳态对肌细胞分泌功能的影响。初步实验结果提示TfR1是心肌细胞铁离子摄入的主要通路并在维持心肌功能中发挥关键作用。本研究将为阐明肌肉铁稳态代谢机制及分子网络提供坚实数据，为肌肉相关疾病防治寻找新策略。

铁是最早被发现的生命必需微量元素之一，是合成血红蛋白、肌红蛋白等重要分子的原料，也是一系列氧化还原反应中许多酶的辅酶。铁元素参与氧的运输、细胞呼吸、核酸合成等重要生命活动，因此铁代谢稳态调控在维持机体新陈代谢中具有重要作用。本课题围绕肌肉等重要组织器官微量元素代谢的分子调控机制具体开展研究，通过条件性基因敲除小鼠结合生化分子生物学与人群流行病学方法，课题组主要发现了肌肉等器官铁稳态代谢调控新机制，发展了“铁稳态失衡-铁死亡-疾病”理论体系，为相关重大疾病的防治提供了新思路与新策略。此外，项目研究成果还丰富了重要器官锌、锰代谢调控分子网络机制，并揭示了铁等金属元素稳态失衡在人群心血管疾病等重大慢病中的关键作用。总体上，“肌肉铁稳态代谢的生理及分子机制”研究项目执行顺利，圆满完成了既定的研究计划，在论文发表及人才培养等均有优秀成果产出，并有后续研究仍在继续。本项目资助期间，课题组在Hepatology、PNAS、BMC Medicine、Antioxidants & Redox Signaling、Obesity Reviews、PLoS Genetics等主流学术刊物发表论文36篇，主编译专著3部，主办国际学术会议2次，申请相应发明专利9项，获得授权专利3项。