Manganese Transport and Toxicity

描述(申请人提供)：我们提出了海普西丁调节锰代谢的假说。越来越多的体外研究证据表明，作为海普西丁调节靶标的铁门蛋白在锰的运输中发挥了作用。我们对HFE-/-小鼠的活体研究强烈支持这一观点。我们将使用Flatiron(FFe+/-)小鼠作为铁蛋白缺乏症的遗传模型，直接测试其在锰代谢中的功能。虽然铁转运蛋白在肠内皮细胞和网状内皮系统的巨噬细胞铁输出中的作用已经确定，但其在肝细胞中的活性还有待充分研究，在肝细胞中也高表达该转运蛋白。我们假设，在肝脏中，铁门蛋白在胆汁中锰的排泄中起作用，这是一种已知的体内平衡途径，可以清除体内多余的金属。根据我们的模型，我们推测在炎症过程中，循环中的锰水平被海普西丁抑制，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建新的范式来解释锰稳态的分子基础，从而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.