Manganese Transport and Toxicity

摘要 锰稳态必须平衡，以防止过量金属的神经毒性作用，同时提供 为生长和发育提供充足的营养。已经确定，锰水平强烈地 受铁代谢的影响。我们已经发现，血液锰水平降低的个人， 遗传性血色病因为这种铁超载疾病是由遗传缺陷引起的， 铁调素-膜铁转运蛋白轴，我们推测铁调节激素铁调素也调节锰 体内平衡锰的过剩和充足之间的平衡是通过肝胆排泄来调节的 的金属，但洞察分子机制只是最近才获得。基于新 关于肝脏中锰转运蛋白的信息，我们提出了一个肝胆金属的创新模型， 分泌物拟议的项目将直接测试我们的假设模型矢量锰贩运 并进一步确定铁调素在金属稳态中的作用。目标是：1）确定 Mn转运蛋白Slc 40 a1（ferroportin）、Slc 30 a10（ZnT 10）、Slc 39 a8（Zip 9）和Slc 39 a14的细胞定位 （Zip 14）在极化的WIF-B肝细胞中; 2）定义WIF-B肝细胞中锰转运蛋白的调节， HH患者肝脏样品;和3）确定Mn转运蛋白在肝胆转运中的分子功能 使用在Transwell过滤器上生长的“培养物”单层中的HepaRG肝细胞的模型系统。

ABSTRACT Manganese homeostasis must be balanced to prevent neurotoxic effects of excess metal while providing sufficient nutrition for growth and development. It has been established that manganese levels are strongly influenced by iron metabolism. We have found that blood manganese levels are reduced in individuals with hereditary hemochromatosis. Because this iron overload disease arises from genetic deficiencies in the hepcidin-ferroportin axis, we theorize that the iron regulatory hormone hepcidin also regulates manganese homeostasis. The balance between excess and sufficiency of manganese is regulated by hepatobiliary excretion of the metal, but insight into the molecular mechanism has only recently been obtained. Based on new information about manganese transporters in the liver, we propose an innovative model for hepatobiliary metal secretion. The proposed project will directly test our hypothetical model for vectorial manganese trafficking across the hepatocyte and further define hepcidin’s role in metal homeostasis. The goals are: 1) To identify the cellular localization of the Mn transporters Slc40a1 (ferroportin), Slc30a10 (ZnT10), Slc39a8 (Zip9) and Slc39a14 (Zip14) in polarized WIF-B hepatocytes; 2) To define the regulation of Mn transporters in WIF-B hepatocytes and HH patient liver samples; and 3) To determine the molecular function of Mn transporters in hepatobiliary transport model system using HepaRG hepatocytes in a “sandwich-culture” monolayer grown on Transwell filters.