Influence of HFE on metal pharmacokinetics and neurotoxicity

摘要 我的研究兴趣围绕金属毒理学和生理学为基础的中心 药代动力学-药效学（PBPK）建模。我的目标是进一步调查 金属吸收的药代动力学与环境中金属诱导的毒性之间的关系 暴露和遗传易感性（基因-环境相互作用）。这个问题的主要假设是 研究建议摄入和吸入金属的吸收在HFE缺乏时上调 因此，HFE突变（C282 Y; H62 D）的患者更容易受到神经毒性的影响。 环境金属暴露。 指导阶段：在哈佛公共卫生学院的指导阶段，我将获得 在新的研究领域的知识和专业知识，补充我过去的培训，是必不可少的， 作为独立调查员的未来研究研究领域是：i）生物化学测定， DMT 1的表达及其通过铁状态的调节，以及ii）来自各种组织的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)为了确定DMT 1在十二指肠、呼吸和嗅觉上皮中的蛋白水平， 以及10周龄的Hfe-/-和Hfe+/+小鼠，喂食缺铁、基础和含铁饮食。 2)测定和比较59 Fe和54 Mn的药代动力学和组织分布 通过静脉内注射和胃内注射给予Hfe-/-和Hfe+/+“野生型”对照小鼠 灌胃 3)确定并比较54 Mn给药后的药代动力学和组织分布， Hfe-/-和Hfe+/+小鼠通过鼻内和鼻内滴注。 独立阶段：我的长期职业目标是在一所学术机构获得终身教职。 在这里，我将能够扩大我研究领域，培训和指导研究生和本科生 学生，并与我的学术同行合作和学习。利用培训和取得的成果 在指导阶段，HFE缺乏增强锰神经毒性的假设将被 测试. 4)测试Mn后Hfe-/-和Hfe+/+小鼠的运动协调和学习/记忆能力 exposure. 5)研究Mn中毒对Hfe-/-和Hfe+/+小鼠中枢神经系统的损害。 6)开发基于生理学的药代动力学/药效学模型，以描述 Hfe对金属的药代动力学和毒性。 通过直接检测HFE对金属吸收和处置的影响及其相关性， 神经毒性，这项调查将提供基础，以评估未来的风险，健康影响，由于 从环境来源和遗传脆弱性的金属吸收。该研究具有广泛的相关性， HFE相关血色素沉着症和铁超载的管理。

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.