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: 8065486
• 负责人: Clement Eugene Furlong
• 金额: $ 35.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065486
• 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; 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.

基因的二氧氧蛋白酶家族（PON1，PON2和PON）位于人类染色体上。 PON1代谢有机磷（OP）化合物，氧化脂质，药物和法定人数 因素。 PON1多态性会影响催化效率和血浆水平。后果 两个PON2编码区多态性尚不清楚。 PON1在肝脏中合成，分泌到 血浆，而PON2在包括大脑在内的组织中无处不在。 PON2不水解操作 但具有强大的抗氧化特性。帕金森氏病患者发现PON1状态已改变 与男性对照受试者相比。拟议的研究旨在提高我们对PON1，PON2的了解 PON在确定对环境诱导的神经毒性和神经退行性的敏感性方面起作用 疾病。具体目标1遵循我们对PON1状态与关系的研究 华盛顿州农药处理者队列中对OP毒性的敏感性。除了监视 血浆胆碱酯酶水平，我们将包括一个新的定量质谱法（MS）分析 蛋白质生物标志物通过运营商和航空公司事件的暴露修饰。具体目标2调查 PON1和羧酸酯酶在调节杀虫剂混合物的毒性方面的相互作用。具体目标3 研究PON1在调节毒死rif虫的产前发育神经毒性中的作用，其中 假设大坝的PON1状态对于胎儿保护很重要。这些对PON1 null的研究 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调查了POS 1、2的作用 帕金森氏病（PD）中的3和HDL组成。作为我们以前研究的后续措施 与对照组相比，男性PD患者的PON1状态差异，我们将使用基于MS的基于MS 蛋白质组学方法检查PD受试者与匹配对照中的HDL组成。小鼠缺乏pon 还将测试蛋白质对多巴胺能神经毒素MPTP的敏感性。特定目标5涉及 与Project 5合作，以在植物系统中表达稳定的兔子PON1，以修复OP溢出。