补铁药物抑制PrPC表达在Prion病中的作用及机制研究

Prion病是由蛋白质PrPC构象变化为PrPSc引起的神经退行性疾病，至今不可治愈。PrPC由Prnp基因编码，抑制其表达是治疗此病的重要策略。申请人近期研究发现，Prion病小鼠脑内铁还原酶Cybrd1和Steap3的表达呈持续性提高; 体外用补铁剂处理感染了Prion的神经元，减少转铁蛋白受体Tfr1，能下调Prnp mRNA水平，减少PrPC和PrPSc; 给正常小鼠外周补铁，也能减少脑内Prnp mRNA和PrPC。推测脑内铁代谢对Prion病程发展起重要作用。因此，本项目拟运用Prion病小鼠模型明确外周补铁减少脑内PrPC和PrPSc，进而减缓神经免疫反应和改善铁代谢失调的作用，阐明相关信号通路，进一步明确铁代谢调控分子Tfr1、Cybrd1、Steap3等在Prion病程中的作用机制，并在体内观察以其为新靶点的治疗效应。预期成果为此类神经退行性疾病的药物研发提供新的方向。

Prion diseases are a group of fatal neurodegenerative diseases. So far, no effective therapy exists for prion disease. The pathogenic scrapie prion protein (PrPSc） is an isoform of the normal cellular prion protein (PrPC). PrPC is encoded by the Prnp gene..The expression level of PrPC is a key factor affecting the neurotoxicity of PrPSc. Reducing PrPC expression is an important therapeutic strategy for prion disease. Recently, the applicant has found that the expression of iron reductase Cybrd1 and Steap3 in the brain of mice with Prion disease showed continuous increase. In vitro treatment of Prion-infected neurons with iron supplements reduced the transferrin receptor Tfr1, down-regulated Prnp mRNA levels, and thus reduced PrPC and PrPSc. Peripheral iron supplementation of normal mice also reduced Prnp mRNA and PrPC in the brain. We speculated that iron metabolism in the brain plays an important role in the development of Prion disease. Therefore, we intend to use a mouse model of Prion disease to clarify that peripheral iron supplementation reduces PrPC and PrPSc in the brain, thereby slowing down immune responses and improving iron metabolism disorders, and clarifying related signal pathways. Further, to clarify the mechanism of iron metabolism regulating molecules Tfr1, Cybrd1, Steap3, etc. during Prion disease progression, and observe the therapeutic effect of using them as new targets in vivo. The expected results provide a new direction for the drug development of such a group of neurodegenerative diseases.