Influence of HFE on metal pharmacokinetics and neurotoxicity

描述（由申请人提供）：候选人的研究兴趣围绕金属毒理学和基于生理学的药代动力学-药效学（PBPK）建模。 目的是进一步研究在环境暴露和遗传易感性（基因-环境相互作用）背景下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，摄入和吸入金属的吸收在HFE缺乏时上调，使得HFE突变（C282 Y; H62 D）的患者更容易受到环境金属暴露诱导的神经毒性的影响。 指导阶段：在哈佛公共卫生学院的指导阶段，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将补充他们过去的培训，并对我未来作为独立调查员的研究至关重要。研究领域包括：i）用于DMT 1的表达及其通过铁状态的调节的生物化学测定，和ii）来自各种暴露途径（特别是吸入）的金属吸收的药代动力学。具体目标是： 1)测定喂食缺铁、基础和铁负荷饲料的3、6和10周龄Hfe-/-和Hfe+/+小鼠的十二指肠、呼吸道和嗅觉上皮中DMT 1的蛋白水平。 2)确定并比较通过静脉注射和胃内灌胃给予Hfe-/-和Hfe+/+“野生型”对照小鼠的59 Fe和54 Mn的药代动力学和组织分布。 3)确定并比较通过鼻内和气管内滴注给予Hfe-/-和Hfe+/+小鼠的54 Mn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学术机构获得终身教职，在那里他们将能够扩大他们的研究领域，培训和指导研究生和本科生，并与我的学术同行合作和学习。利用在指导阶段获得的培训和结果，HFE缺乏增强锰神经毒性的假设将被测试。 4)检测锰暴露后Hfe-/-和Hfe+/+小鼠的运动协调和学习记忆能力。 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对金属药代动力学和毒性的作用。 通过直接研究HFE对金属吸收和处置及其相关神经毒性的影响，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产生影响的风险提供基础。该研究与HFE相关血色素沉着症和铁超载的管理具有广泛的相关性。 公共卫生相关性：这项调查将提供基础，以评估未来的风险，健康影响由于金属吸收环境来源和遗传脆弱性。该研究与HFE相关血色素沉着症和铁超载的管理具有广泛的相关性。

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.