Project 1: Biomarkers of Susceptibility to Environmentally-Induced Diseases

项目 1：环境诱发疾病易感性的生物标志物

• 批准号: 7622773
• 负责人: Clement Eugene Furlong
• 金额: $ 34.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622773
• 关键词: Acetylcholinesterase; Address; Affect; Agricultural Workers; Aircraft; Alternative Splicing; Antioxidants; Behavior; Behavioral; Biochemical; Biological Markers; Blood; Brain; Butyrylcholinesterase; Carboxylic Ester Hydrolases; Carotid Artery Diseases; Chemosensitization; Chlorpyrifos; Cholinesterases; Chromosomes, Human, Pair 7; Code; Collaborations; Coupled; Development; Diazinon; Disease; Drug Formulations; Drug or chemical Tissue Distribution; Engineering; Enzymes; Epidemiologic Studies; Erythrocytes; Escherichia coli; Exons; Exposure to; Gel; Gene Expression; Gene Family; Genetic Polymorphism; High Density Lipoproteins; Histocytochemistry; Histopathology; Human; Human Chromosomes; Hydrolysis; Individual; Insecticides; Knock-out; Knockout Mice; Knowledge; Liquid substance; Liver; Lubricants; Mass Spectrum Analysis; Measures; Mediating; Modification; Molecular; Monitor; Mus; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurons; Neurotoxins; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; Organophosphorus Compounds; Oryctolagus cuniculus; Paraoxon; Parkinson Disease; Patients; Pesticides; Pharmaceutical Preparations; Plants; Plasma; Post-Translational Protein Processing; Predisposition; Pregnancy; Progress Reports; Property; Protein Analysis; Proteins; Proteomics; Recombinants; Research; Risk Factors; Role; Sarin; Seasons; Site; Soman; Surface; System; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Transgenic Plants; Translating; Variant; Washington; Western Blotting; adduct; aryldialkylphosphatase; base; carboxylesterase; cohort; design; detoxication; developmental neurotoxicity; diazoxon; esterase; farm worker; fetal; follow-up; indexing; inorganic phosphate; malaoxon; male; mouse model; nerve agent; neurotoxic; neurotoxicity; novel; oxidized lipid; prenatal; pup; pyrethroid; remediation; research study

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.

对氧磷酶基因家族（PON1、PON2 和 PONS）位于人类 7 号染色体上。HDL 相关 PON1 代谢有机磷 (OP) 化合物、氧化脂质、药物和群体感应 因素。 PON1 多态性影响催化效率和等离子体水平。的后果 两个 PON2 编码区多态性未知。 PON1在肝脏中合成并分泌到 血浆中，而 PON2 普遍表达于组织中，包括大脑。 PON2 不水解 OP 但具有很强的抗氧化性能。发现男性帕金森病患者的 PON1 状态发生改变 与男性对照受试者相比。拟议的研究旨在增加我们对 PON1、PON2 的了解 PONS 在确定对环境引起的神经毒性和神经退行性疾病的易感性方面发挥作用 疾病。具体目标 1 是我们对 PON1 状态和 PON1 之间关系的研究的后续行动 华盛顿州农药处理人员群体对有机磷农药毒性的敏感性。除了监控 血浆胆碱酯酶水平，我们将包括一种新颖的定量质谱（MS）分析 蛋白质生物标志物因 OP 处理人员和航空事故的暴露而发生变化。具体目标 2 调查 PON1 和羧酸酯酶在调节杀虫剂混合物毒性中的相互作用。具体目标 3 检查 PON1 在调节毒死蜱 oxon 的产前发育神经毒性中的作用，其中 据推测，母鼠的 PON1 状态对于胎儿保护很重要。这些研究 PON1 无效 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。具体目标 4 研究 PON 1、2 的作用 3 和 HDL 组成在帕金森病 (PD) 中的作用。作为我们之前研究的后续 显示男性 PD 患者与对照组相比 PON1 状态存在差异，我们将使用基于 MS 的 蛋白质组学方法检查 PD 受试者与匹配对照的 HDL 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 与 Project 5 合作，在植物系统中表达稳定的兔 PON1，以修复 OP 泄漏。