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: 9262452
• 负责人: Young Ah Seo
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262452
• 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; tenure track; 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） 候选人的研究目标是在环境暴露和神经变性发病机制的背景下研究锰（Mn）诱导的运输和神经毒性。帕金森病是一种神经退行性疾病，影响全球400万人，其中包括北美的100万人。长期暴露于锰导致神经行为缺陷，类似于帕金森病。 锰在大脑中的积累是帕金森病的已知危险因素。尽管人们越来越认识到与锰暴露相关的问题，但对其潜在机制知之甚少。 来自体外研究的累积证据表明，膜铁转运蛋白（Fpn），一种已知的铁输出蛋白， 锰运输。 候选人的初步研究直接支持这一模式。她发现，缺乏Fpn的flatiron小鼠具有较低的肠道吸收和减少的Mn的胆汁排泄。 她的体外外源性表达研究表明，野生型Fpn防止锰的积累和细胞毒性，而熨斗突变Fpn（H32 R）完全消除这种细胞保护作用。 然而，Fpn缺乏如何影响神经毒性和神经变性尚不清楚。基于研究者的体外和动物模型研究，候选人假设Fpn功能的丧失增强了脑Mn积累，导致Mn神经毒性。 Fpn中已知的人类突变引起膜铁转运蛋白病，一种遗传性血色病。 候选人假设的一个推论是，Fpn突变的个体更容易受到与锰暴露相关的神经毒性和神经退行性疾病的影响。为了验证这些假设，候选人将联合收割机结合使用多巴胺能SH-SY 5 Y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Mn转运蛋白发挥作用以及Fpn功能丧失增强大脑Mn积累和神经毒性的主要假设。指导阶段将提供培训，并建立实验基础，以探索独立阶段这一假设的人类后果。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中锰的神经毒性。 候选人的长期职业目标是在学术机构获得终身教职，在那里她将能够扩大她的研究领域，培训和指导研究生和本科生，并与她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，她将测试Fpn缺乏增强Mn神经毒性的假设，使得具有Fpn突变的个体更容易患神经退行性疾病。 具体目的是：3）确定已知的人Fpn突变对体外Mn神经毒性的影响。4)探讨Fpn基因变异与帕金森病的关系。