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: 8845296
• 负责人: Clement Eugene Furlong
• 金额: $ 1.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845296
• 关键词: Acetylcholinesterase; Address; Affect; Agricultural Workers; Aircraft; Antioxidants; Behavior; Behavioral; Biochemical; Biological Markers; Blood; Brain; Butyrylcholinesterase; Carboxylic Ester Hydrolases; Carotid Artery Diseases; Chemosensitization; Chlorpyrifos; Cholinesterases; Chromosomes, Human, Pair 7; Code; Collaborations; Development; Diazinon; Disease; Epidemiologic Studies; Erythrocytes; Exons; Exposure to; Gene Expression; Gene Family; Genetic Polymorphism; High Density Lipoproteins; Histopathology; Human; Human Chromosomes; Individual; Insecticides; Knock-out; Knockout Mice; Knowledge; 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; Risk Factors; Role; Seasons; System; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Washington; 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; quorum sensing; research study

The paraoxonase family of genes (PON1, PON2 and PONS) is located on human chromosome 7. HDL-associated PON1 metabolizes organophosphorus (OP) compounds, oxidized lipids, drugs and quorum-sensing 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（PON 1、PON 2和脑桥）位于人7号染色体上。HDL相关的PON 1代谢有机磷（OP）化合物，氧化脂质，药物和群体感应因子。PON 1多态性影响催化效率和血浆水平。两个PON 2编码区多态性的后果是未知的。PON 1在肝脏中合成并分泌到血浆中，而PON 2在包括脑在内的组织中广泛表达。PON 2不水解OP，但具有很强的抗氧化性能。与男性对照组相比，男性帕金森病患者的PON 1状态发生了改变。拟议的研究旨在增加我们对PON 1，PON 2和脑桥在确定环境诱导的神经毒性和神经退行性疾病的易感性方面的功能的了解。具体目标1跟进我们的研究的关系，PON 1的状态和敏感性OP毒性的队列华盛顿州农药处理。除了监测血浆胆碱酯酶水平，我们还将包括一种新的定量质谱（MS）分析， 蛋白质生物标志物被OP处理者和航空公司事件中的暴露所修饰。具体目标2研究了PON 1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研究了PON 1在调节毒死蜱oxon的产前发育神经毒性中的作用，其中假设母体的PON 1状态对胎儿保护很重要。这些对PON 1缺失小鼠和人源化PON 1转基因小鼠（tgHuPON 1-Q192和tgHuPON 1-R192）的研究包括生物化学、行为、组织病理学和分子终点。具体目标4研究脑桥1、2的作用 和3与帕金森病（PD）HDL组成的关系。作为我们先前研究的后续研究，这些研究显示男性PD患者与对照组相比PON 1状态存在差异，我们将使用基于MS的蛋白质组学方法来检查PD受试者与匹配对照组的HDL组成。还将测试缺乏PON蛋白的小鼠对多巴胺能神经毒素MPTP的敏感性。具体目标5涉及与项目5合作，在植物系统中表达稳定的兔PON 1，用于修复OP溢出。