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

项目摘要 帕金森病（PD）至少有两种类型，家族性和散发性（sPD）。到目前为止， 占大多数病例，并逐渐被视为几个基因的结果， 它们与环境的相互作用，包括广泛使用的农药。一个这样的代理是 百草枯（PQ）是一种在发展中国家和美国广泛使用的除草剂。数据 将PQ暴露与sPD联系起来的流行病学研究尚不确定，我们将证明 PQ暴露本身可能不足以产生sPD。至少还有一个因素是铁 [Fe]在黑质，pars rectata（SNc）中的含量。SNc中的铁被认为是 sPD的另一个危险因素。体外研究表明，PQ和Fe 协同杀死SNc中的多巴胺神经元，这是PD的病理标志。在 我们提出的研究，我们将表明，PQ破坏铁稳态在SNc和， 该组织中铁的增加是PQ神经毒性的定义。本研究的总体目标是 鉴定赋予PQ诱导的差异易感性的基因和基因网络 增加SNc中的Fe。为了解决这个问题，我们将研究PQ的效果- C57 BL/6和DBA/2亲本衍生的40个重组自交系铁含量增加 菌株第一个实验将展示百草枯广泛的、基于遗传的变异性， 增加SNc中的Fe。第二个实验将表明，基于PQ的破坏 多巴胺能神经元与PQ相关的SNc中Fe稳态破坏的程度有关。 接下来，我们将通过微阵列分析研究百草枯对基因表达的影响。 黑质、腹侧部，然后结合QTL分析基因表达 与QTL的PQ增加铁在SNc，我们将阐明生化途径参与 以及阐明遗传标记， 增加（降低）SNc中多巴胺神经元损伤的风险

Project Summary 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