铁过载介导Ferroptosis途径对非输血依赖性地中海贫血红系造血的损伤效应及机制研究

无效红细胞生成所致贫血引起的铁过载可致脏器功能损害，已成为非输血依赖性地中海贫血（NTDT）治疗中的难题。我们前期研究表明我国NTDT患者贫血明显，铁过载严重。研究显示铁过载可介导地贫患者红系造血损伤，机制尚未明确。Ferroptosis是新发现的铁依赖性细胞死亡模式。本课题拟以铁过载介导NTDT患者造血损伤作为研究对象，在NTDT患者和地贫鼠模型中，检测铁代谢、细胞活性氧、红系造血、Ferroptosis水平等，评估铁过载介导Ferroptosis途径对NTDT红系造血损伤效应。进一步在患者红系细胞和鼠模型中，运用药物干预等方法分析铁过载介导Ferroptosis途径对NTDT红系造血损伤机制。本课题通过探讨铁过载介导Ferroptosis途径对NTDT红系造血损伤效应及机制，验证铁螯合剂、Ferroptosis抑制剂等逆转铁过载损伤效应，为治疗铁过载介导NTDT红系造血损伤提供新思路。

Iron overload caused by ineffective erythropoiesis can lead to organ dysfunction and has become an intractable issue in the treatment of non-transfusion-dependent thalassemia (NTDT). Our previous study has shown that NTDT patients in China have severe anemia and a high burden of iron overload. Studies have proved that iron overload can damage bone marrow erythropoiesis in thalassemia patients, but the exact mechanisms are still unclear. Ferroptosis is a recently recognized form of regulated cell death dependent on lethal reactive oxygen species (ROS) derived from iron metabolism. Our study is to select the iron overload-mediated erythropoietic injury in NTDT patients as study subject, through examining iron metabolism, ROS, erythropoiesis, Ferroptosis level and other experimental methods, we will assess the damage effect of iron overload-mediated Ferroptosis pathway on NTDT erythropoiesis in NTDT patients and thalassaemic mouse model. Furthermore, in NTDT erythroid cells and mouse model, through drug intervention, we try to explore the mechanisms of iron overload-mediated Ferroptosis pathway on the injury of NTDT erythropoiesis. This project will investigate the effect of iron overload-mediated Ferroptosis pathway on the injury of erythropoiesis in NTDT and its mechanism and verify that iron chelators, Ferroptosis inhibitors reverse the effects of iron overload injury, and provide new ideas for clinical treatment of iron overload mediated NTDT erythropoietic damage.