铁稳态代谢中Hepcidin负调控因子的功能机制研究

Iron homeostasis is essential for maintaining human health. Both positive and negative regulators tightly mediate iron balance. Hepcidin is the liver secreted central hormone in regulating iron homeostasis and is mainly regulated by TGF-β signal pathway. In iron metabolism, the physiological functions of TGF-β inhibitors including Smad7 remain unknown. Therefore, we constructed liver-specific Smad7 gene knockout mice. We have observed the physiological functions of Smad7 in negatively regulating hepcidin. To screen additional negative regulators of hepcidin, we applied high throughput RNA sequencing technology in the liver tissue of the Smad7 deficient mice. A panel of novel hepcidin inhibitors was also identified. In this proposal, we aim to systematically investigate the function of these newly identified hepcidin inhibitors using physiological relevant multiple cell lines and other iron gene knockout mice, which has been established in the lab. The findings of this study could provide potential preventive and therapeutic targets for iron-related disorders and diseases.

铁稳态对于维护机体健康至关重要。Hepcidin是肝脏分泌的调节铁代谢的核心激素，其分泌表达主要受BMP/Smad信号通路的调控。体外实验报道Smad7作为抑制因子可调控Hepcidin表达，但Smad7及其它负调控因子如何影响铁稳态的体内调控及其机制却知之甚少。为此，我们构建了Smad7肝细胞基因敲除小鼠，发现敲除Smad7可解除对Hepcidin的抑制；进一步的高通量RNA测序分析筛选出在Smad缺失的肝组织中的多个新的负调控因子，并已初步验证部分因子对Hepcidin的抑制效应。本项目拟运用多种铁基因敲除小鼠模型，开展体内外功能实验，系统深入研究Hepcidin负调控因子网络系统的生理功能及分子机制，为铁稳态失衡疾病的防治提供新靶点。

本项目按研究计划圆满完成，在青年项目资助下发表了4篇原创性研究论文。在铁稳态代谢中Hepcidin负调控因子的功能机制研究方面：通过基因敲除小鼠结合转录组测序，发现Smad7可以通过负调控铁调素Hepcidin维持铁代谢稳态，还首次揭示Smad6、Bambi和Follistatin在特定情况下参与Hepcidin的负向调控并发挥维持铁稳态代谢的作用（Journal of Cellular and Molecular Medicine 2018，并列第一作者）。铁代谢紊乱相关疾病病理机制研究方面：采集并确认了3个中国遗传性血色病家系，发现了中国患者基因突变新位点并阐述了其引发遗传性血色病的机制（Blood Cells, Molecules, and Diseases 2017，并列第一作者）；参与运用多种基因敲除小鼠模型发现高铁状态以及遗传性血色病铁过载可诱发肝脏的肝细胞及巨噬细胞发生铁死亡（Ferroptosis）（Hepatology 2017，第二作者）； 通过将近3000例前列腺癌的病例对照样本研究，发现血清铁蛋白联合前列腺特异性抗原（PSA）可提高前列腺癌预测的准确性（Oncotaget 2017，并列第一作者）。项目资助期间，项目负责人安鹏博士当选了中国生物物理学会-生物微量元素分会理事，担任知名专业学术期刊《American Journal of Clinical Nutrition》和《Scientific Reports》杂志审稿人。