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

描述（由申请人提供）：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，sPD占大多数病例，并且越来越被认为是几个基因及其与环境相互作用的结果，包括广泛使用的农药。其中一种除草剂是百草枯（PQ），这是一种在发展中国家和美国广泛使用的除草剂。流行病学研究将PQ暴露与sPD联系起来的数据尚无定论，我们将表明仅PQ暴露可能不足以产生sPD。至少还有一个因素是黑质致密物（SNc）中的铁含量[Fe]。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协同作用，杀死SNc中的多巴胺神经元，SNc是PD的病理标志。在拟议的研究中，我们将证明PQ破坏SNc中的铁稳态，并且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确定基因和基因网络，这些基因和基因网络赋予pq诱导SNc中铁增加的差异易感性。为了解决这一问题，我们将研究PQ-增加铁对40株由C57BL/6和DBA/2亲本菌株衍生的重组自交系的影响。第一个实验将是在SNc中显示百草枯增加的铁的广泛的、基于遗传的变异性。第二个实验将表明，多巴胺神经元的pq破坏与SNc中pq相关的铁稳态破坏程度有关。接下来，我们将通过微阵列分析研究百草枯对黑质、紧部基因表达的影响，然后将基因表达的QTL分析与SNc中pq -增加铁的QTL分析结合起来，我们将阐明百草枯-铁神经毒性的生化途径，并阐明表明SNc中多巴胺神经元损伤风险增加（降低）的遗传标记

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