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

基本信息

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
项目类别：
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

项目摘要

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的背景下研究锰（MN）诱导的转运和神经毒性。帕金森氏病是一种神经退行性疾病，影响了全球400万人，其中包括北美100万人。长期暴露于MN导致的神经性缺陷类似于帕金森氏病。 MN在大脑中的积累是帕金森氏病的已知危险因素。尽管人们对与MN暴露有关的问题的认识越来越大，但对基本机制知之甚少。从体外研究中积累的证据表明，已知的铁出口商铁托蛋白（FPN）起作用在MN运输中。候选人的初步研究直接支持该模型。她发现缺乏FPN的扁铁小鼠具有较低的肠吸收和Mn的胆道排泄降低。她的体外外源性表达研究表明，野生型FPN可防止MN积累和细胞毒性，而扁平铁突变FPN（H32R）完全消除了这种细胞保护作用。但是，FPN缺乏如何影响神经毒性和神经退行性。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MN的积累，从而导致MN神经毒性。 FPN中已知的人类突变会导致铁蛋白疾病，这是一种遗传性血色素肿瘤的形式。候选人假设的推论是，患有FPN突变的个体更容易受到与MN暴露相关的神经毒性和神经退行性疾病的影响。为了检验这些假设，候选人将结合使用多巴胺能SH-SY5Y细胞，扁平铁小鼠和人类受试者与帕金森氏病的使用。在K99的指导阶段，在哈佛公共卫生学院的Wessling-Resnick博士的指导下，候选人将检验一个主要假设，即FPN充当大脑中的MN转运蛋白，而FPN功能的丧失可以增强脑MN的积累和神经毒性。指导阶段将提供训练并建立实验基础，以探索独立阶段的人类后果。具体目的是：1）检查FPN在体内脑Mn转运中的作用。 2）在暴露后表征扁平铁小鼠中的MN神经毒性。候选人的长期职业目标是在一个学术机构中获得任期教师职位，在那里她将成为扩大自己的研究，培训和指导毕业生和本科生的领域，并与她的学术同伴合作并学习。利用在指导阶段获得的训练和结果，她将检验以下假设：FPN缺乏增强了MN神经毒性，使FPN中突变的个体更容易受到神经退行性疾病的影响。具体目的是：3）确定已知人类FPN突变对体外MN神经毒性的影响。 4）探索FPN基因变体与帕金森氏病之间的关联。