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Neural Toxicity of Paraquat is Related to Iron Regulation in the Midbrain

百草枯的神经毒性与中脑的铁调节有关

基本信息

批准号：
9265854
负责人：
BYRON C JONES
金额：
$ 57.3万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-24 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265854
关键词：
Address Affect Animals Area Biochemical Pathway Biological Biological Assay Biological Markers Brain Candidate Disease Gene Code Complex Custom Developing Countries Diet Dietary Iron Dose Environment Exhibits Family Gene Activation Gene Expression Microarray Analysis Gene Expression Profiling Gene Proteins Genes Genetic Genetic Markers Genetic Techniques Genetic Transcription Genotype Glial Fibrillary Acidic Protein Goals Herbicides Homeostasis Human Human Genome Idiopathic Parkinson Disease Immune response In Vitro Inbreeding Individual Individual Differences Injectable Iron Iron-Binding Proteins Lead Link Liver Measures Mediating Messenger RNA Midbrain structure Modeling Molecular Mus Neurodegenerative Disorders Neurons Paraquat Parkinson Disease Pathologic Pathway interactions Pesticides Physiology Play Population Predisposition Preventive Intervention Protein Isoforms Proteins Protocols documentation Publishing Quantitative Trait Loci RNA RNA Splicing Recombinant Inbred Strain Recombinants Regulation Research Resistance Risk Risk Factors Rodent Role Saline Severities Spleen Substantia nigra structure System Techniques Testing Tissue-Specific Gene Expression Tissues Toxic effect Transferrin Untranslated RNA Variant Work Yin aged analytical tool base differential expression dopaminergic neuron epidemiologic data epidemiology study experimental study gene environment interaction genetic analysis genetic approach improved innovation insight killings mRNA Expression male mouse genome nervous system disorder network models neurochemistry neuron loss neurotoxicity novel oxidative damage pars compacta prevent public health relevance putamen relating to nervous system resistant strain response toxicant trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): There are at least two types of Parkinson's disease (PD), familial and sporadic (sPD). By far, sPD accounts for the majority of cases and is becoming to be seen as the result of several genes and their interaction with the environment, including widely used pesticides. One such agent is paraquat (PQ), an herbicide used widely in developing countries and also in the USA. The data from epidemiological studies linking PQ exposure with sPD are inconclusive and we will show that PQ exposure alone is likely insufficient to produce sPD. At least one other factor is iron content [Fe] in the substantia nigra pars compacta (SNc). Iron in the SNc is considered to be another risk factor for sPD. Studies conducted in vitro have shown that PQ and Fe act synergistically in killing dopamine neurons in the SNc, the pathological hallmark of PD. In the proposed research, we will show that PQ disrupts iron homeostasis in the SNc and that the increased iron in this tissue is what defines PQ neurotoxicity. The overall goal of this research is to identify genes and gene networks that confer differential susceptibility to PQ-induced increased Fe in the SNc. In order to address the problem, we will study the effect of PQ- increased Fe in 40 recombinant inbred strains derived from C57BL/6 and DBA/2 parental strains. The first experiment will be to show wide, genetic-based variability in paraquat- increased Fe in the SNc. The second experiment will be to show that PQ-based destruction of dopamine neurons is related to the extent of PQ-related disruption of Fe homeostasis in the SNc. We will next investigate the effects of paraquat on gene expression by microarray analysis in the substantia nigra, pars compacta and then by combining QTL analysis for the gene expression with QTL for PQ-increased Fe in the SNc, we will elucidate the biochemical pathways involved in paraquat-iron neurotoxicity as well as elucidating genetic markers that indicate increased (decreased) risk for damage to dopamine neurons in the SNc

描述(申请人提供)：至少有两种类型的帕金森病(PD)，家族性和散发性(SPD)。到目前为止，SPD占了大多数病例，并正被视为几个基因及其与环境相互作用的结果，包括广泛使用的杀虫剂。其中一种药剂是百草枯(PQ)，这是一种在发展中国家和美国广泛使用的除草剂。将PQ暴露与SPD联系起来的流行病学研究的数据是不确定的，我们将证明PQ单独暴露可能不足以产生SPD。至少还有一个因素是黑质致密部(SNC)中的铁含量。SNC中的铁被认为是SPD的另一个风险因素。在体外进行的研究表明，PQ和Fe在杀死黑质多巴胺神经元方面具有协同作用，而黑质是帕金森病的病理标志。在拟议的研究中，我们将证明PQ扰乱了SNC中的铁稳态，而这个组织中增加的铁是定义PQ神经毒性的原因。这项研究的总体目标是确定对PQ诱导的SNC中铁含量增加具有不同易感性的基因和基因网络。为了解决这一问题，我们将研究PQ-增铁对来自C57BL/6和DBA/2亲本菌株的40个重组近交系菌株的影响。第一个实验将在SNC中显示百草枯增加的铁的广泛的、基于遗传的变异性。第二个实验将证明，基于PQ的多巴胺神经元的破坏与PQ相关的SNC中铁稳态的破坏程度有关。接下来，我们将通过微阵列分析来研究百草枯对黑质致密部基因表达的影响，然后通过结合对黑质致密部基因表达的QTL分析和对PQ增加的铁的QTL分析，我们将阐明涉及百草枯铁神经毒性的生化途径，并阐明表明黑质多巴胺神经元损伤风险增加(降低)的遗传标记。