Project 3: Molecular Mechanisms

项目3：分子机制

基本信息

批准号：
8309379
负责人：
LUCIO G COSTA
金额：
$ 4.99万
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：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309379
关键词：
Acetylcholinesterase Adult Affect Apoptosis Behavior Biological Biometry Child Chlorpyrifos Cohort Studies Communication Core Facility Development Environmental Health Enzymes Exposure to Gene Expression Hippocampus (Brain)In Vitro Insecticides Life Modeling Molecular Mus Nervous system structure Neuraxis Neurites Neuroglia Neuronal Differentiation Neurons Neurotoxins Organism Organophosphates Oxidative Stress Oxygen Pathway interactions Pesticides Predisposition Public Health Reporting Research Research Support Risk Risk Assessment Risk Management Rodent Role Series Signal Pathway Staging Toxic effect Translating Washington Work analog base developmental neurotoxicity human stem cells in vitro Model insight nervous system development neurodevelopment neurogenesis neurotoxicity pesticide exposure pesticide induced neurotoxicity postnatal precursor cell prenatal research study toxicant

项目摘要

Organophosphates pesticides (OP) are among the most widely applied pesticides worldwide and in Washington state. In adults, OPs are recognized to act as neurotoxicants through their ability to inhibit the enzyme, acetylcholinesterase (AChE). In the developing organism it is still unknown whether OP-induced developmental neurotoxicity is a consequence of AChE inhibition. Increased reports from child cohort studies suggest gestational exposures to pesticides are of public health concern. Current risk assessment and management strategies may not be optimal with the use of AChE inhibition as a regulatory anchor. This project will examine the relationship between AChE inhibition and neurotoxicity in depth, across pre- and postnatal developmental life stages. The overall hypothesis of our proposal is that pesticide exposure alters neurodevelopment and behavior in rodents by interfering with cellular pathways controlling proliferation, differentiation and apoptosis in the CNS during critical "windows of susceptibility" and that these mechanisms are independent of AChE inhibition. Using in vitro neurodevelopmental-stage specific models for both pre and postnatal developmental periods, we propose to assess the role of OP-induced oxidative stress and its consequential impact on these important cellular pathways, which underlie CNS development. The specific aims are: (l)to investigate the direct effects of OPs on neurite outgrowth, neuronal proliferation and viability in neurodevelopment-stage specific in vitro models (human stem cells, mouse neuronal precursor cells, and rodent hippocampal neurons);(2)to elucidate the impacts of OP-induced oxidative stress and effects on neurogenesis; (3)to examine developmental stage specific OP impacts on proliferation and differentiation gene expression pathways; and(4) to investigate OP effects on glial-neuronal communication. These proposed experiments will provide significant new insight into the mechanisms of OP-induced neurotoxicity and the role of AChE inhibition during pre- and post-natal neurodevelopment. Working closely with the Biostatistics, Modeling and Risk Characterization Facility Core, results from these studies will be integrated and translated into developing biological and pathway based models relevant for risk assessment across developmental periods and across species.

有机磷农药 (OP) 是全世界和华盛顿州应用最广泛的农药之一状态。在成人中，OP 通过抑制酶而被认为是神经毒剂，乙酰胆碱酯酶（AChE）。在发育中的有机体中，目前尚不清楚 OP 是否会诱导发育神经毒性是 AChE 抑制的结果。越来越多的儿童队列研究报告表明妊娠接触农药是一个公共卫生问题。当前的风险评估和管理策略可能不会使用 AChE 抑制作为调节锚是最佳的。该项目将检查关系深入研究 AChE 抑制和神经毒性之间的关系，涵盖产前和产后发育生命阶段。这我们提议的总体假设是，接触农药会通过以下方式改变啮齿类动物的神经发育和行为：在关键时期干扰控制中枢神经系统增殖、分化和凋亡的细胞途径 “易感性窗口”并且这些机制独立于 AChE 抑制。体外使用针对产前和产后发育期的神经发育阶段特定模型，我们建议评估 OP 诱导的氧化应激的作用及其对这些重要细胞途径的影响，是中枢神经系统发育的基础。具体目标是： (l) 研究 OP 对神经突生长的直接影响，神经发育阶段特定体外模型（人类干细胞、小鼠神经元前体细胞和啮齿动物海马神经元）；（2）阐明OP诱导的氧化的影响压力及其对神经发生的影响； (3)检查发育阶段特定OP对增殖和增殖的影响分化基因表达途径； (4) 研究OP对神经胶质-神经元通讯的影响。这些拟议的实验将为 OP 诱导的机制提供重要的新见解。神经毒性以及 AChE 抑制在产前和产后神经发育过程中的作用。密切合作借助生物统计学、建模和风险表征设施核心，这些研究的结果将整合并转化为开发与风险评估相关的生物和途径模型发育时期和跨物种。