Regulation of systemic iron homeostasis by microRNA-122

系统铁平衡必须精确平衡，以防止缺铁和铁超载疾病，这是世界上最常见的疾病。肝肽激素hepcidin通过控制十二指肠铁吸收和巨噬细胞铁释放来维持血浆铁浓度。Hepcidin的转录受遗传性血色素沉着病相关蛋白[Hfe， TfR2和Hfe2 (haemjuvelin)]、高促红细胞生成活性和炎症因子的转录调节。我们现在首次表明，全身铁代谢也受到非编码microRNA miR-122的控制，miR-122在肝脏中大量表达：小鼠体内miR-122的有效和特异性消耗会导致小细胞增多，降低浆膜和肝脏铁水平，增加hepcidin、HFE和HFE2的mRNA表达。本研究计划的目的是：(1)通过转录组学和蛋白质组学实验方法，鉴定能够解释miR-122缺失小鼠生理变化的mlR-122靶mrna；(2)测试miR-122耗竭是否可以用于恢复小鼠铁过载；(3)研究小鼠铁过载时其他差异表达的mirna在维持全身铁代谢中的作用。我们期望获得miRNAs对铁稳态调节的基本见解，以及miRNAs在逆转遗传性血色素沉着病模型中铁过载的治疗潜力。

Systemic Iron homeostasis must be precisely balanced to prevent diseases of iron deficiency and Iron overload, which belong to the most frequent disorders worldwide. The hepatic peptide hormone hepcidin maintains plasma Iron concentrations by controlling duodenal Iron absorption and macrophage Iron release. Hepcidin transcription Is regulated transcriptionally by the hereditary hemochromatosis associated proteins [Hfe, TfR2 and Hfe2 (hemojuvelin)], high erythropoietic activity and Inflammatory cytokines. For the first time we now show that systemic Iron metabolism is also controlled by a non-coding microRNA, miR- 122, which Is abundantly expressed in the liver: efficient and specific depletion of miR-122 In the mouse causes microcytosis, reduced serosal and liver iron levels as well as Increased mRNA expression of hepcidin, HFE and HFE2.The alms of this research proposal are (1) to identify mlR-122 target mRNAs that explain the physiological changes observed in miR-122 depleted mice by applying transcriptomic and proteomic experimental approaches; (2) to test whether miR-122 depletion can be applied to revert murine Iron overload and (3) to study the role of additional miRNAs differentially expressed In response to murine iron overload In maintaining systemic Iron metabolism. We expect to gain fundamental Insights into the regulation of iron homeostasis by miRNAs and the therapeutic potential miRNAs may have in reversing iron overload in a hereditary hemochromatosis disease model.