Influence of HFE on metal pharmacokinetics and neurotoxicity

摘要 我的研究兴趣集中在金属毒理学和生理学基础上 药代动力学-药效学(PBPK)模型。我的目标是进一步调查这段关系 环境背景下金属吸收与金属毒性之间的药代动力学 暴露和遗传易感性(基因-环境相互作用)。这其中的主要潜在假设是 研究建议是，摄入和吸入的金属的吸收在HFe缺乏时被上调 因此，HFE(C282Y；H62D)突变的患者更容易受到 环境金属暴露。 指导阶段：在哈佛公共卫生学院的这笔赠款的指导阶段，我将获得 新研究领域的知识和专业知识是对我过去的培训的补充，对 我未来作为一名独立调查员的学习。研究领域是：i)生化分析 DMT1的表达及其铁状态的调节II)不同来源金属吸收的药代动力学 接触途径，特别是吸入途径。具体目标是： 1)测定DMT1在十二指肠、呼吸和嗅觉上皮中的蛋白水平。 10周龄HFe-/-和HFe+/+小鼠分别饲喂缺铁、基础饲料和铁负荷饲料。 2)测定并比较~(59)Fe和~(54)Mn的药代动力学和组织分布 HFe-/-和HFe+/+“野生型”对照小鼠静脉注射和灌胃给药 盖奇。 3)测定并比较54Mn在体内的药代动力学和组织分布。 HFe-/-和HFe+/+小鼠经鼻腔和气管内滴注。 独立阶段：我的长期职业目标是在一家学术机构获得终身教职 在那里我将能够扩大我的研究领域，培训和指导研究生和本科生 学生，并与我的学术同行合作并向他们学习。利用所获得的培训和成果 在指导阶段，高铁缺乏增强锰神经毒性的假设将是 测试过。 4)检测锰中毒后HFe-/-和HFe+/+小鼠的运动协调能力和学习记忆能力 曝光。 5)研究锰中毒对HFe-/-和HFe+/+小鼠中枢神经系统的损伤。 6)开发基于生理学的药代动力学/药效学模型来描述 HFE对金属药代动力学和毒性的影响。 通过直接检测HFe对金属及其相关物质的吸收和处置的影响 神经毒性，这项调查将为评估未来因以下原因而对健康造成的影响风险提供基础 环境来源的金属吸收和遗传脆弱性。这项研究具有广泛的关联性 高铁相关性血色素沉着症和铁超载的处理。

ABSTRACT My research interests center around metal toxicology and physiology-based pharmacokinetic-pharmacodynamic (PBPK) modeling. My goals are to further investigate the relationship between pharmacokinetics of metal absorption and metal-induced toxicity in the context of environmental exposure and genetic susceptibility (gene-environment interactions). The major underlying hypothesis of this research proposal is that absorption of ingested and inhaled metals is up-regulated upon HFE-deficiency such that patients with mutations in HFE (C282Y; H62D) are more vulnerable to neurotoxicity induced by environmental metal exposure. Mentored phase: During the mentored phase of this grant at the Harvard School of Public Health, I will gain knowledge and expertise in new areas of research that complement my past training and that are essential for my future studies as an independent investigator. The research areas are: i) biochemical assays for expression of DMT1 and its regulation by iron status and ii) pharmacokinetics of metal absorption from various routes of exposure, and inhalation in particular. The specific aims are: 1) To determine protein levels of DMT1 in duodenal, respiratory and olfactory epithelium from 3, 6, and 10 wk-old Hfe-/- and Hfe+/+ mice fed iron-deficient, basal and iron-loaded diets. 2) To determine and compare the pharmacokinetics and tissue distribution of 59Fe and 54Mn administered to Hfe-/- and Hfe+/+ "wild-type" control mice by intravenous injection and by intragastric gavage. 3) To determine and compare the pharmacokinetics and tissue distribution of 54Mn administered to Hfe-/- and Hfe+/+ mice by intranasal and intratracheal instillation. Independent phase: My long-term career goal is to obtain a tenure-track faculty position at an academic institution where I will be able to expand my area of research, train and instruct graduate and undergraduate students, and collaborate with and learn from my academic peers. Utilizing the training and results obtained during the mentored phase, the hypothesis that HFE-deficiency enhances manganese neurotoxicity will be tested. 4) To test motor coordination and learning/memory capacity of Hfe-/- and Hfe+/+ mice after Mn exposure. 5) To examine CNS damage in Hfe-/- and Hfe+/+ mice due to Mn intoxication. 6) To develop a physiology-based pharmacokinetic/pharmacodynamic model to describe the role of Hfe on metal pharmacokinetics and toxicity. By directly examining the influence of HFE on the uptake and disposition of metals and their associated neurotoxicity, this investigation will provide the groundwork to assess the future risk of health effects due to metal absorption from environmental sources and genetic vulnerability. The research has broad relevance to the management of HFE-associated hemochromatosis and iron-overload.