Regulation of systemic iron homeostasis by microRNA-122

系统性铁稳态必须精确平衡，以防止铁缺乏和铁过载疾病，这属于世界上最常见的疾病。肝肽激素铁调素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。铁调素转录受遗传性血色素沉着症相关蛋白[Hfe、TfR 2和Hfe 2（血幼素）]、高红细胞生成活性和炎性细胞因子的转录调节。我们现在第一次表明，全身铁代谢也由非编码microRNA，miR- 122控制，它在肝脏中大量表达：小鼠中miR-122的有效和特异性消耗导致小红细胞增多、血清铁和肝铁水平降低以及铁调素mRNA表达增加，HFE和HFE 2.本研究的目的是（1）应用转录组学和蛋白质组学实验方法鉴定mIR-122靶mRNA，以解释在miR-122缺失小鼠中观察到的生理变化;（2）测试miR-122消耗是否可应用于逆转鼠铁过载和（3）研究响应于鼠铁过载而差异表达的另外的miRNA在维持全身铁代谢中的作用。我们希望通过miRNAs对铁稳态的调节以及miRNAs在逆转遗传性血色病模型中铁超载方面的治疗潜力获得基本的见解。

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.