Influence of HFE on metal pharmacokinetics and neurotoxicity

描述(申请人提供)：应聘者的研究兴趣集中在金属毒理学和基于生理学的药代动力学-药效学(PBPK)建模方面。目的是在环境暴露和遗传易感性(基因-环境相互作用)的背景下，进一步研究金属吸收的药代动力学和金属诱导的毒性之间的关系。这项研究建议的主要基本假设是，HFe缺乏时，摄入和吸入的金属的吸收被上调，因此HFE(C282Y；H62D)突变的患者更容易受到环境金属暴露引起的神经毒性的影响。 指导阶段：在哈佛公共卫生学院这项资助的指导阶段，候选人将获得新研究领域的知识和专业知识，这些知识和专业知识是对他们过去培训的补充，也是我作为一名独立研究人员未来学习所必需的。研究领域包括：1)DMT1表达的生化分析及其铁状态的调节；2)不同暴露途径，特别是吸入过程中金属吸收的药代动力学。具体目标是： 1)测定3、6、10周龄HFe-/-和HFe/HFe小鼠十二指肠、呼吸道和嗅觉上皮中DMT1的蛋白水平。 2)测定和比较HFe-/-和HFe/“野生型”对照小鼠静脉注射和灌胃给药后59Fe和54Mn的药代动力学和组织分布。 3)测定和比较54Mn在HFe-/-小鼠和HFe-/-小鼠体内的药代动力学和组织分布。 独立阶段：候选人的长期职业目标是在一家学术机构获得终身教职，在那里他们将能够扩大自己的研究领域，培训和指导研究生和本科生，并与我的学术同行合作并向他们学习。利用在指导阶段获得的培训和结果，将检验HFe缺乏增强锰神经毒性的假设。 4)检测染锰后HFe-/-和HFe/小鼠的运动协调能力和学习记忆能力。 5)研究锰中毒对HFe-/-和HFe/小鼠中枢神经系统的损害。 6)建立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对金属摄取和处置的影响及其相关的神经毒性，这项调查将为评估未来因环境来源的金属吸收和遗传脆弱性而对健康造成的影响提供基础。这项研究对HFE相关性血色素沉着症和铁超载的治疗具有广泛的相关性。 公共卫生相关性：这项调查将为评估由于环境来源的金属吸收和遗传脆弱性而对健康造成的影响的未来风险提供基础。这项研究对HFE相关性血色素沉着症和铁超载的治疗具有广泛的相关性。

DESCRIPTION (provided by applicant): The candidate's research interests center around metal toxicology and physiology-based pharmacokinetic-pharmacodynamic (PBPK) modeling. The 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, the candidate will gain knowledge and expertise in new areas of research that complement their 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 intra-tracheal instillation. Independent phase: The candidate's long-term career goal is to obtain a tenure-track faculty position at an academic institution where they will be able to expand their 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. Public Health Relevance: 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.