膜蛋白SLC在铁代谢中的功能研究

Iron is an essential trace element found in nearly all living organisms. It is not only required for the synthesis of hemoglobin and myoglobin, but also represented as the cofactor for many key enzymes involved in redox reactions, and therefore is critical for the process of metabolism. Now, although advanced progress had been made on iron research, however, there are still new genes or pathways needed to be investigated and discovered. To find new genes or pathways related to iron metabolism, we used gene chips to screen genes responsive to iron. The array results showed that iron could significantly up-regulate the expression of SLC gene, and this was further validated in primary cultured macrophage and hepatocyte. Moreover, iron could significantly increase the expression of SLC in mouse in vivo. Further, we found that spleen iron in SLC mice was significantly lower than that of wild type control mice while no significant changes was observed in liver iron content. In conclusion, these results showed that iron could affect the expression of SLC, and also indicated that SLC might be involved in macrophage iron metabolism. As a membrane protein, the relationship between SLC and iron metabolism is unclear till now. In this project, we will use cell and SLC mouse models to investigate the role of SLC in iron metabolism. This will further extend our knowledge in basic research of iron metabolism.

铁是机体必需的微量元素之一，它不仅是合成血红蛋白、肌红蛋白的原料，也是氧化还原反应系统中一些关键酶的辅酶，在机体新陈代谢中发挥极为重要的作用。目前，尽管铁代谢方面的研究已经取得了很大进展，但仍旧有很多新的铁代谢相关基因和通路有待研究与发现。为寻找调控铁代谢的新基因或通路，我们利用基因芯片筛选对铁有响应的基因，分析结果显示铁能够显著上调SLC基因的表达，这一结果在体外培养的原代巨噬细胞和肝实质细胞中也得到了充分证实。另外，在小鼠中，我们发现铁也能够显著上调SLC的表达。此外，在SLC敲除小鼠中，我们发现脾脏铁显著降低，肝脏铁变化不明显。综上说明铁能够影响SLC的表达，同时也提示SLC可能参与了巨噬细胞的铁代谢调控。目前，膜蛋白SLC与铁代谢之间的关系还不明确，此课题中，我们将利用细胞和SLC敲除小鼠模型来研究SLC在铁代谢中的作用，进一步丰富基础铁代谢研究。

铁离子是体内产生氧化自由基的重要来源，也是导致机体氧化损伤的重要因素。我们通过基因芯片筛选、细胞铁刺激实验、铁蓄积动物模型等手段系统地证明铁能上调SLC7A11的表达。我们首次以SLC7A11-/-小鼠为模型开展SLC7A11调控铁代谢功能和机制的研究。研究发现：（1）在体内、体外、以及铁过载的疾病模型中，SLC7A11都可以很好地响应铁刺激。（2）SLC7A11在正常生理状态下，对铁代谢基本不产生影响，但在压力刺激下，会对铁代谢产生显著影响。（3）SLC7A11对维持巨噬细胞内的氧化还原稳态极为重要。SLC7A11通过影响巨噬细胞功能影响铁代谢。（4）SLC7A11对造血前体细胞的分化具有重要作用。（5）证实铁过载及血色病小鼠模型中存在铁死亡-Ferroptosis现象，将铁代谢失衡与Ferroptosis联系起来（6）阐明了SLC7A11在Ferroptosis中的作用。（7）揭示了铁、氧化压力与Ferroptosis的关系。综上，本项目系统研究了SLC7A11在铁代谢中的作用，丰富了铁代谢调控网络，对于铁过载疾病的临床治疗具有重要理论指导意义。