Influence of genetic variation on manganese neurotoxicity and Parkinson's disease

遗传变异对锰神经毒性和帕金森病的影响

• 批准号: 8752660
• 负责人: Young Ah Seo
• 金额: $ 8.93万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752660
• 关键词: Address; Affect; Animal Model; Area; Awareness; Basal Ganglia; Biliary; Biology; Brain; Brain region; Cell Death; Cells; Chronic; Disease; Environmental Exposure; Excretory function; Exposure to; Faculty; Foundations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Goals; Health; Hemochromatosis; Hippocampus (Brain); Homeostasis; Human; In Vitro; Individual; Inherited; Institution; Intestinal Absorption; Ion Transport; Iron; Learning; Manganese; Mentors; Mentorship; Metal exposure; Metals; Modeling; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathogenesis; North America; Outcome; Parkinson Disease; Pathogenesis; Patients; Phase; Pilot Projects; Play; Positioning Attribute; Predisposition; Prevention; Public Health Schools; Radiolabeled; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Training; Translating; Work; base; career; cytotoxicity; genetic variant; graduate student; human subject; in vivo; insight; manganese chloride; metal transporting protein 1; neurobehavioral; neuron apoptosis; neurotoxicity; olfactory bulb; peer; prevent; public health relevance; radiotracer; undergraduate student; uptake

DESCRIPTION (provided by applicant) The candidate's research goals are to investigate manganese (Mn)-induced transport and neurotoxicity in the context of environmental exposure and pathogenesis of neurodegeneration. Parkinson's disease is a neurodegenerative disorder affecting four million people worldwide, including one million people in North America. Chronic exposure to Mn results in neurobehavioral deficits similar to Parkinson's disease. Mn accumulation in the brain is a known risk factor for Parkinson's disease. Despite growing awareness of the problems associated with Mn exposure, little is known about the underlying mechanisms. Accumulating evidence from in vitro studies suggests that ferroportin (Fpn), a known iron exporter, plays a role in Mn transport. The candidate's preliminary studies directly support this model. She found that flatiron mice, which are deficient in Fpn, have lower intestinal absorption and reduced biliary excretion of Mn. Her in vitro exogenous expression studies show that wild-type Fpn prevents Mn accumulation and cytotoxicity while the flatiron mutation Fpn (H32R) completely abrogates this cytoprotective effect. However, how Fpn deficiency influences neurotoxicity and neurodegeneration is not understood. Based on the investigators' in vitro and animal model studies, the candidate hypothesize that loss of Fpn function enhances brain Mn accumulation leading to Mn neurotoxicity. Known human mutations in Fpn cause ferroportin disease, an inherited form of hemochromatosis. A corollary to the candidate's hypothesis is that individuals with Fpn mutations are more vulnerable to neurotoxicity and neurodegenerative diseases associated with Mn exposure. To test these hypotheses, the candidate will combine the use of dopaminergic SH-SY5Y cells, flatiron mice, and human subjects with Parkinson's disease. During the K99 mentored phase, under the mentorship of Dr. Wessling-Resnick at Harvard School of Public Health, the candidate will test the major hypothesis that Fpn functions as a Mn transporter in the brain and that loss of Fpn function enhances brain Mn accumulation and neurotoxicity. The Mentored Phase will provide training and establish the experimental foundation to explore the human consequences of this hypothesis during the Independent Phase. The specific aims are: 1) To examine the role of Fpn in brain Mn transport in vivo. 2) To characterize Mn neurotoxicity in flatiron mice after exposure. The candidate's long-term career goal is to obtain a tenure- track faculty position at an academic institution where she will be abl to expand her area of research, train and instruct graduate and undergraduate students, and collaborate with and learn from her academic peers. Utilizing the training and results obtained during the mentored phase, she will test the hypothesis that Fpn deficiency enhances Mn neurotoxicity such that individuals with mutations in Fpn are more vulnerable to neurodegenerative diseases. The specific aims are: 3) To determine the effects of known human Fpn mutations on Mn neurotoxicity in vitro. 4) To explore the associations between Fpn gene variants and Parkinson's disease.

描述（由申请人提供） 该候选人的研究目标是研究环境暴露和神经退行性疾病发病机制中锰 (Mn) 诱导的转运和神经毒性。帕金森病是一种神经退行性疾病，影响着全世界 400 万人，其中包括北美的 100 万人。长期接触锰会导致类似于帕金森病的神经行为缺陷。 大脑中锰的积累是帕金森病的已知危险因素。尽管人们越来越意识到与锰暴露相关的问题，但对其潜在机制知之甚少。 体外研究积累的证据表明，铁转运蛋白 (Fpn)（一种已知的铁输出蛋白）在其中发挥着重要作用 在锰的运输中。 候选人的初步研究直接支持了这一模型。她发现，缺乏 Fpn 的熨斗小鼠肠道吸收率较低，胆汁排泄锰也减少。 她的体外外源表达研究表明，野生型 Fpn 可防止 Mn 积累和细胞毒性，而扁铁突变 Fpn (H32R) 则完全消除了这种细胞保护作用。 然而，Fpn 缺乏如何影响神经毒性和神经变性尚不清楚。根据研究人员的体外和动物模型研究，候选者假设 Fpn 功能的丧失会增强大脑中 Mn 的积累，从而导致 Mn 神经毒性。 已知的人类 Fpn 突变会导致铁转运蛋白疾病，这是一种遗传性血色素沉着病。 候选人假设的一个推论是，具有 Fpn 突变的个体更容易遭受与锰暴露相关的神经毒性和神经退行性疾病。为了测试这些假设，候选人将结合使用多巴胺能 SH-SY5Y 细胞、熨斗小鼠和患有帕金森病的人类受试者。 在 K99 指导阶段，在哈佛大学公共卫生学院 Wessling-Resnick 博士的指导下，候选人将测试 Fpn 在大脑中作为锰转运蛋白的主要假设，以及 Fpn 功能的丧失会增强大脑中锰的积累和神经毒性。指导阶段将提供培训并建立实验基础，以探索该假设在独立阶段对人类的影响。具体目的是：1）研究Fpn在体内脑锰转运中的作用。 2) 表征暴露后熨斗小鼠的锰神经毒性。 候选人的长期职业目标是在学术机构获得终身教授职位，在那里她将能够扩大研究领域，培训和指导研究生和本科生，并与学术同行合作并向其学习。利用指导阶段获得的培训和结果，她将检验以下假设：Fpn 缺乏会增强 Mn 神经毒性，从而导致 Fpn 突变的个体更容易患神经退行性疾病。 具体目标是： 3) 确定已知的人类 Fpn 突变对体外锰神经毒性的影响。 4) 探讨Fpn基因变异与帕金森病的关联。