Manganese Transport and Toxicity

描述（由申请人提供）：我们提出hepcidin调节锰代谢的假设。从体外研究中积累的证据表明，铁转运蛋白，hepcidin调节的目标，在锰的运输中起作用。我们对Hfe-/-小鼠的体内研究有力地支持了这一观点。我们将使用flatiron （ffe+/-）小鼠作为铁转运蛋白缺乏的遗传模型，直接测试其在锰代谢中的功能。虽然铁转运蛋白在肠上皮细胞和网状内皮系统巨噬细胞的铁输出中的作用已经确立，但其在肝细胞中的活性尚未得到充分探索，肝细胞中铁转运蛋白也高度表达。我们假设，在肝脏中，铁转运蛋白在胆道锰排泄中起作用，这是一种清除体内多余金属的已知稳态途径。基于我们的模型，我们推测在炎症过程中循环锰水平被hepcidin抑制，这一观点得到了已知宿主-病原体相互作用的很好支持。最后，我们将确定我们在Hfe基因敲除小鼠中观察到的嗅觉锰吸收增加的机制。形成我们研究基础的原始新思想将通过创造新的范式来解释锰稳态的分子基础，对金属代谢领域产生强大的持续影响。

DESCRIPTION (provided by applicant): We advance the hypothesis that hepcidin regulates manganese metabolism. Accumulating evidence from in vitro studies suggests that ferroportin, the target of hepcidin regulation, plays a role in the transport of manganese. Our in vivo studies of Hfe-/- mice strongly support this idea. We will directly test its function in manganese metabolism using flatiron (ffe+/-) mice as a genetic model of ferroportin deficiency. While ferroportin function in iron export by intestinal enterocytes and macrophages of the reticuloendothelial system has been established, its activity has yet-to-be fully explored in hepatocytes where the exporter also is highly expressed. We hypothesize that in the liver, ferroportin functions in biliary excretion of manganese, a known homeostatic pathway that clears excess metal from the body. Based on our model, we speculate that circulating manganese levels are suppressed during inflammation by hepcidin, an idea that is well-supported by known host-pathogen interactions. Finally, we will determine the mechanism responsible for increased olfactory manganese absorption we have observed in Hfe knockout mice. The original new ideas forming the basis of our research will have a powerful sustaining influence on the field of metal metabolism by creating new paradigms to explain the molecular basis for manganese homeostasis.