Influence of HFE on metal pharmacokinetics and neurotoxicity

HFE 对金属药代动力学和神经毒性的影响

• 批准号: 8536288
• 负责人: Jonghan Kim
• 金额: $ 24.26万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536288
• 关键词: 3-nitrotyrosine; Age; Area; Award; Behavioral; Biochemical; Biological Assay; Biological Availability; Biological Markers; Blood; Breathing; Complement; Data; Deoxyguanosine; Diet; Dopamine; Drug Kinetics; Drug or chemical Tissue Distribution; Environmental Exposure; Faculty; Future; Gastrointestinal tract structure; Genes; Genetic Predisposition to Disease; Goals; Grant; Health; Hemochromatosis; Immunohistochemistry; Individual; Inhalation Exposure; Institution; Intoxication; Investigation; Iron; Iron Overload; Knowledge; Learning; Lung; Manganese; Measurement; Measures; Memory; Mentors; Metal exposure; Metals; Modeling; Motor; Mus; Mutation; Olfactory Epithelium; Oxidative Stress; Partition Coefficient; Patients; Pharmacodynamics; Phase; Physiological; Physiology; Positioning Attribute; Problem behavior; Proteins; Public Health Schools; Regulation; Research; Research Personnel; Research Proposals; Research Training; Respiratory System; Respiratory tract structure; Risk; Role; Route; SLC11A2 gene; Site; Source; Structure of respiratory epithelium; Susceptibility Gene; Testing; Tissues; Toxic effect; Toxicology; Training; Western Blotting; absorption; base; career; divalent metal; feeding; gastrointestinal; gene environment interaction; graduate student; indexing; interest; intravenous injection; iron metabolism; metal poisoning; morris water maze; neurotoxicity; peer; pharmacodynamic model; response; undergraduate student; uptake; wasting

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.

抽象的 我的研究兴趣集中在金属毒理学和基于生理学的基础上 药代动力学 - 药效学（PBPK）建模。我的目标是进一步调查关系 在环境的背景下，金属吸收的药代动力学与金属诱导的毒性之间 暴露和遗传敏感性（基因 - 环境相互作用）。这是主要的基本假设 研究建议是，在HFE缺乏效率下，吸收和吸入金属的吸收被上调 因此，HFE突变的患者（C282Y; H62D）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这笔赠款的指导阶段，我将获得 在新的研究领域的知识和专业知识，这是我过去培训的补充，这对于 我作为独立研究者的未来研究。研究领域是：i）生化测定 DMT1的表达及其对铁状态的调节和II）来自各种金属吸收的药代动力学 暴露途径，尤其是吸入。具体目的是： 1）确定十二指肠，呼吸道和嗅觉上皮的DMT1的蛋白质水平 以及10周龄的HFE - / - 和HFE+/+小鼠喂养铁缺乏的基底和铁饮食。 2）确定和比较59FE和54MN的药代动力学和组织分布 通过静脉注射和胃内施用对HFE - / - 和HFE+/+“野生型”对照小鼠 宣传。 3）确定和比较54MN的药代动力学和组织分布 HFE - / - 和HFE+/+小鼠通过鼻内和气管内滴注。 独立阶段：我的长期职业目标是在学术上获得终身任职教师职位 我将能够扩大我的研究领域，培训和指导研究生和本科的机构 学生，并与我的学术同龄人合作并学习。利用培训和获得的结果 在指导阶段，HFE缺乏性增强锰神经毒性的假设将是 测试。 4）测试HFE - / - 和HFE+/+小鼠Mn之后的运动协调和学习/记忆能力 接触。 5）检查由于Mn中毒而引起的HFE - / - 和HFE+/+小鼠的CNS损伤。 6）开发基于生理学的药代动力学/药效学模型来描述 金属药代动力学和毒性的HFE。 通过直接检查HFE对金属摄取和处置及其相关的影响 神经毒性，这项调查将为评估由于 来自环境来源和遗传脆弱性的金属吸收。这项研究与 与HFE相关的血色素沉着病和铁超负荷的管理。