Project 1: Biomarkers of Susceptibility to Environmentally-Induced Diseases

对氧磷酶基因家族(PON1、PON2和PONS)位于人类7号染色体上。 PON1代谢有机磷(OP)化合物、氧化脂质、药物和量子传感 各种因素。PON1基因多态性影响催化效率和血浆水平。其后果是 这两个PON2编码区的多态性是未知的。PON1在肝脏中合成并分泌到 而PON2在包括脑在内的组织中普遍表达。PON_2不能水解OP 但具有很强的抗氧化性。男性帕金森氏症患者PON1状态发生改变 与男性对照受试者比较。建议的研究旨在增加我们对PON1、PON2 脑桥在决定环境所致神经毒性和神经退行性变易感性中的作用 疾病。具体目标1跟进我们关于PON1状态和 华盛顿州一群农药操作者对有机磷中毒的易感性。除了监控之外 血浆胆碱酯酶水平，我们将包括一种新的定量质谱仪(MS)分析 蛋白质生物标记物因暴露在OP操作者和航空事故中而改变。特定目标2调查 PON1和羧酸酯酶在调节杀虫剂混剂毒性中的相互作用。具体目标3 研究PON1在调节毒死蜱毒杀作用中的作用，其中 假设水坝的PON1状态对胎儿保护很重要。PON1为空的这些研究 小鼠和人源化PON1转基因小鼠(tgHuPON1-Q192和tgHuPON1-R192)包括生化， 行为、组织病理学和分子终点。特定目标4调查桥1、2的作用 3和高密度脂蛋白在帕金森病(PD)中的组成。作为我们之前研究的后续， 显示男性PD患者的PON1状态与对照组相比存在差异，我们将使用基于MS的 蛋白质组学方法检测帕金森病受试者与匹配对照组的高密度脂蛋白组成。缺乏PON的小鼠 还将测试蛋白质对多巴胺能神经毒素MPTP的敏感性。具体目标5涉及一项 与项目5合作，在植物系统中表达稳定的兔子PON1，以补救OP泄漏。

The paraoxonase family of genes (PON1, PON2 and PONS) is located on human chromosome 7. HDLassociated PON1 metabolizes organophosphorus (OP) compounds, oxidized lipids, drugs and quorumsensing factors. PON1 polymorphisms affect catalytic efficiency and plasma levels. The consequences of the two PON2 coding region polymorphisms are unknown. PON1 is synthesized in liver and secreted into plasma, whereas PON2 is ubiquitously expressed in tissues, including brain. PON2 does not hydrolyze OPs but has strong antioxidant properties. PON1 status was found to be altered in male Parkinson's patients compared with male control subjects. The proposed studies aim to increase our knowledge of PON1, PON2 and PONS functions in determining susceptibility to environmentally-induced neurotoxicity and neurodegenerative diseases. Specific Aim 1 follows up on our studies on the relationship of PON1 status and susceptibility to OP toxicity in a cohort of Washington State pesticide handlers. In addition to monitoring plasma cholinesterase levels, we will include a novel quantitative mass spectrometric (MS) analysis of protein biomarkers modified by exposures in OP handlers and airline incidents. Specific Aim 2 investigates the interplay of PON1 and carboxylesterase in modulating the toxicity of insecticide mixtures. Specific Aim 3 examines the role of PON1 in modulating prenatal developmental neurotoxicity of chlorpyrifos oxon, where PON1 status of dams is hypothesized to be important for fetal protection. These studies with PON1 null mice and humanized PON1 transgenic mice (tgHuPON1-Q192 & tgHuPON1-R192) include biochemical, behavioral, histopathological and molecular end-points. Specific Aim 4 investigates the role of PONs 1, 2 and 3 and HDL composition in Parkinson's disease (PD). As a follow-up on our previous studies that showed differences in PON1 status in male PD patients compared with controls, we will use an MS-based proteomic approach to examine HDL composition in PD subjects vs. matched controls. Mice lacking PON proteins will also be tested for sensitivity to the dopaminergic neurotoxin MPTP. Specific Aim 5 involves a collaboration with Project 5 to express stable rabbit PON1 in plant systems for remediating OP spills.