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（PON 1、PON 2和脑桥）位于人7号染色体上。HDL相关 PON 1代谢有机磷（OP）化合物、氧化脂质、药物和群体感应 因素PON 1多态性影响催化效率和血浆水平。的后果 两个PON 2编码区多态性是未知的。PON 1在肝脏中合成并分泌到肝脏中。 P0 N 2在血浆中广泛表达，而P0 N 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。男性帕金森病患者PON 1状态改变 与男性对照组相比。这些研究的目的是增加我们对PON 1、PON 2 和脑桥神经元在确定环境诱导的神经毒性和神经退行性变的易感性中的作用 疾病具体目标1跟进我们关于PON 1状态与 华盛顿州农药处理者队列中OP毒性的易感性。除了监测 血浆胆碱酯酶水平，我们将包括一个新的定量质谱（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调查 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 检查PON 1在调节毒死蜱oxon的产前发育神经毒性中的作用，其中 母体的PON 1状态被假设为对胎儿保护很重要。这些PON 1无效的研究 小鼠和人源化PON 1转基因小鼠（tgHuPON 1-Q192和tgHuPON 1-R192）包括生物化学， 行为学、组织病理学和分子学终点。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。作为我们之前研究的后续， 显示男性PD患者PON 1状态与对照组相比存在差异，我们将使用基于MS的 蛋白质组学方法来检查PD受试者与匹配对照中的HDL组成。PON缺失小鼠 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 与项目5合作，在植物系统中表达稳定的兔子PON 1，用于修复OP泄漏。