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

项目摘要 帕金森氏病(PD)至少有两种类型，即家族性和散发性。到目前为止，SPD 导致了大多数病例，并逐渐被认为是几个基因和 它们与环境的相互作用，包括广泛使用的杀虫剂。其中一个代理是 百草枯(PQ)，一种在发展中国家和美国广泛使用的除草剂。数据 流行病学研究将PQ暴露与SPD联系起来是不确定的，我们将证明 光是PQ暴露很可能不足以产生SPD。至少还有一个因素是铁。 黑质致密部[Fe]含量(SNC)。SNC中的铁被认为是 SPD的另一个风险因素。体外研究表明，PQ和Fe起作用 协同作用杀死黑质多巴胺神经元，帕金森病的病理标志。在 拟议的研究，我们将证明PQ扰乱SNC中的铁稳态，并且PQ 这种组织中铁含量的增加是PQ神经毒性的定义。这项研究的总体目标是 识别对PQ诱导的不同易感性的基因和基因网络 增加了SNC中的铁。为了解决这个问题，我们将研究PQ的影响- 来自C57BL/6和DBA/2亲本的40个重组自交系的铁含量增加 菌株。第一个实验将展示百草枯广泛的、基于遗传的变异。 增加了SNC中的铁。第二个实验将展示基于PQ的破坏 多巴胺神经元与PQ相关的黑质体内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基因表达的影响 然后结合QTL对黑质、致密部的基因表达进行分析 利用PQ增加的铁在SNC中的QTL，我们将阐明涉及的生化途径 百草枯-铁神经毒性的研究，以及阐明表明 黑质多巴胺神经元受损风险增加(降低)

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