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Biomarkers of Organophosphate-Adducted Proteins

有机磷加合蛋白的生物标志物

基本信息

批准号：
8121757
负责人：
charles mark thompson
金额：
$ 13.55万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121757
关键词：
Accounting Acetylcholinesterase Acute Address Age Aging Agriculture Antibodies Biochemical Biological Biological Markers Blood Blood Tests Carbamates Cells Chemicals Child Cholinergic Receptors Cholinesterases Chronic Detection Diagnostic Procedure Diagnostic tests Dose Environmental Health Erythrocytes Esters Event Exposure to Food Contamination Goals Grant Health Human Insecticides Isotopically-Coded Affinity Tagging Lead Liquid substance Mass Spectrum Analysis Measures Methods Molecular Monitor Neuroblastoma Neurologic Organ Organophosphates Outcome Pathway interactions Pattern Peptides Pesticides Phosphorylation Poison Control Centers Poisoning Proteins Proteome Public Health Radiolabeled Regulation Reporter Reporting Research Research Personnel Risk Risk Assessment Role Safety Saliva Science Policy Serum Site Structure Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Trust adduct base combat nerve gas neurotoxicity programs radiotracer toxic organophosphate insecticide exposure trait true biomarker

项目摘要

The short-term goals of this application are to identify adducted and altered protein biomarkers that correlate with organophosphate (OP) insecticide exposure and to use these biomarkers to generate antibodies to validate the detection of these biomarkers in biological fluids. Over 100 million pounds of OP insecticides are used each year but lead to over 25,000 reports to poison control centers each year including 10,000 involving children under age six. These reports only account for acute poisoning events and do not include low dose or chronic exposures. In addition to general exposure and food contamination, the safety of OPs is a large public health concern because OPs share chemical traits, structure and biological mechanism with nerve gas agents. These concerns are elevated by an array of neurologic and non-neurologic sequelae that have been reported in connection with exposure to OPs. To combat, monitor and provide therapeutic intervention, a blood cholinesterase test (BCT) has been conducted for decades. However, the test is limited and inadequate to assess OP exposure and its shortcomings identified by an EPA report questioned the merit of the BCT and suggested the need to examine true biomarkers of exposure. At this time, there is a serious void in effective tests of OP exposure. New tests are needed that are sensitive, selective, operate in real time and are based on reliable, well-characterized OP-biomarkers derived from exacting molecular events that correlate with cellular, tissue, organ or systemic toxicity. The long range goal of our research is to identify OP-adducted and/or OP-altered protein biomarkers that are associated with OP-induced sequelae and to develop diagnostic methods and tests that assess the human health risk and aid therapeutic action. For the proposed grant period, we will address the following specific aims: SA 1. Show that OP's result in highly specific OP-AChE adducts that can be identified and differentiated by antibodies. SA2. Identify and characterize OP-adducted protein biomarkers in SH-SY5Y neuroblastoma cells using OP-reporter molecules. SA3. Identify and characterize OP-protein biomarkers from human saliva, human serum and human erythrocytes and SA4. Prepare customized antibodies that recognize OP-adducted proteins identified in SA-II and SA-III and develop efficient diagnostic tests to identify and quantify OP-protein adducts.

这项应用的短期目标是识别相关的加合和改变的蛋白质生物标记物与有机磷(OP)杀虫剂接触，并使用这些生物标志物产生抗体验证这些生物标志物在生物体液中的检测。超过1亿磅的有机磷杀虫剂每年使用，但每年向中毒控制中心报告超过25,000起，其中包括10,000起涉及六岁以下的儿童。这些报告仅说明急性中毒事件，不包括低剂量或慢性暴露。除了一般暴露和食物污染外，有机磷农药的安全性还包括一个大的公共卫生问题，因为有机磷农药的化学特性、结构和生物学机制与神经毒剂。一系列神经性和非神经性后遗症加剧了这些担忧已被报道与接触有机磷农药有关。抗击、监测和提供治疗干预措施，血液胆碱酯酶试验(BCT)已经进行了几十年。然而，这项测试是有限的不足以评估OP暴露及其缺陷，EPA的一份报告质疑 BCT的优点，并建议有必要检查暴露的真实生物标志物。这个时候，有一个 OP暴露的有效测试中存在严重的空洞。需要灵敏的、有选择性的、在实时和基于可靠的、特征良好的OP-生物标记物，源自严格的分子与细胞、组织、器官或全身毒性相关的事件。我们研究的长期目标是识别OP加成和/或OP改变的蛋白质生物标记物与OP引起的后遗症相关，并开发诊断方法和测试来评估人类健康风险和辅助治疗行动。在拟议的授权期内，我们将解决以下具体问题目标：SA 1.表明OP的结果是高度特异的OP-AChE加合物，可以被鉴定和通过抗体区分的。SA2.SH-SY5Y中OP加合物蛋白生物标志物的鉴定与鉴定使用OP报告分子的神经母细胞瘤细胞。SA3.识别和表征OP-蛋白生物标志物来自人唾液、人血清和人红细胞以及SA4。准备定制的抗体，识别SA-II和SA-III中识别的OP加成蛋白，并开发有效的诊断测试来识别并对OP蛋白加合物进行量化。