Manganese Transport and Toxicity

锰的运输和毒性

• 批准号: 9126034
• 负责人: Marianne Wessling-Resnick
• 金额: $ 15.09万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126034
• 关键词: Adult; Agonist; Air; Alleles; Bile fluid; Biliary; Binding; Blood; Blood Circulation; Brain; Complex; Dietary Iron; Disease; Enterocytes; Excretory function; Genes; Genetic; Genetic Models; Growth and Development function; Health; Hepatocyte; Hereditary Disease; Hereditary hemochromatosis; Homeostasis; Hormones; Human; In Vitro; Inflammation; Inflammatory Response; Intestinal Absorption; Intestines; Intrathecal Injections; Iron; Iron Overload; Knockout Mice; Liver; Manganese; Membrane; Metabolism; Metals; Modeling; Molecular; Mus; Nervous System Trauma; Nutrient; Pathway interactions; Physiological; Play; Population; Process; Regulation; Research; Reticuloendothelial System; Risk; Role; Route; Signal Transduction; Source; Surface; Testing; Toxic effect; Variant; absorption; base; caucasian American; hepcidin; in vivo; intestinal epithelium; iron deficiency; macrophage; metal metabolism; metal transporting protein 1; neurotoxic; pathogen; toxicant; uptake

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.

描述（由申请人提供）：我们提出了铁调素调节锰代谢的假设。来自体外研究的累积证据表明铁调素调节的靶点膜铁转运蛋白在锰的转运中起作用。我们对Hfe-/-小鼠的体内研究强烈支持这一观点。我们将使用flatiron（ffe+/-）小鼠作为膜铁转运蛋白缺乏症的遗传模型，直接测试其在锰代谢中的功能。虽然已经确定了膜铁转运蛋白在肠上皮细胞和网状内皮系统的巨噬细胞的铁输出中的功能，但其活性尚未在肝细胞中充分探索，其中输出者也高度表达。我们推测，在肝脏中，ferroportin在胆汁排泄锰中起作用，这是一种已知的体内平衡途径，可以清除体内多余的金属。基于我们的模型，我们推测，在炎症过程中，铁调素抑制了循环锰水平，这一想法得到了已知宿主-病原体相互作用的充分支持。最后，我们将确定我们在Hfe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，从而对金属代谢领域产生强大的持续影响。