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

基本信息

批准号：
8254484
负责人：
Clement Eugene Furlong
金额：
$ 31.44万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-07 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254484
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 quorum sensing remediation research study

项目摘要

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.

基因的二氧谁酶家族（PON1，PON2和PON）位于人类7。HDL相关PON1的人类染色体上，代谢有机磷（OP）化合物（OP）化合物，氧化的脂质，药物和法定人数。 PON1多态性会影响催化效率和血浆水平。两个PON2编码区多态性的后果尚不清楚。 PON1在肝脏中合成并分泌成血浆，而PON2在包括大脑在内的组织中无处不在。 PON2不水解操作，但具有强抗氧化特性。与男性对照组相比，男性帕金森患者的PON1状态被改变。拟议的研究旨在提高我们对PON1，PON2和PON的知识在确定对环境诱发的神经毒性和神经退行性疾病的敏感性方面的作用。具体目标1遵循我们对华盛顿州农药处理者队列中PON1状态和OP毒性易感性关系的研究。除了监测血浆胆碱酯酶水平外，我们还将包括新的定量质谱（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研究了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。特定目标3研究了PON1在调节毒死rif虫Oxon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小鼠和人源化PON1转基因小鼠的研究（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。作为我们先前研究的后续研究，该研究表明，与对照组相比，雄性PD患者的PON1状态差异，我们将使用基于MS的蛋白质组学方法检查PD受试者与匹配对照组中的HDL组成。缺乏PON蛋白的小鼠还将测试对多巴胺能神经毒素MPTP的敏感性。特定目标5涉及与项目5的合作，以在植物系统中表达稳定的兔子PON1，以修复OP溢出。