PARATHION EXPOSURE: MECHANISMS OF TOXICTY AND TREATMENT

描述(由申请人提供)：对硫磷有机磷杀虫剂已被NINDS对抗计划确定为对平民最优先的化学威胁之一。急性接触对硫磷可导致死亡、严重癫痫发作、脑损伤、认知缺陷和癫痫，是恐怖组织故意利用进行大规模平民接触的主要风险。故意污染食物和水源以及高楼大厦是灾难性恐怖袭击的主要威胁。这项研究计划将对预防接触对硫磷造成的死亡率和发病率产生重大影响，并将为我们了解介导对硫磷毒性的分子机制开辟一个新的视野。我们建议建立第一个大鼠急性对硫磷中毒的存活模型，并利用该模型开发预防死亡率和发病率的治疗方法。该项目的突破性进展是利用这种对硫磷生存模型发现了一种分子机制，这种机制可能会介导对硫磷毒性的许多严重影响。我们发现，对硫磷毒性引起海马神经元内质网钙释放(CICR)的持续增加，这种分子变化导致海马神经元在暴露后一周以上形成钙平台期。我们建议证明这种改变的钙信号是接触对硫磷的许多疾病的基础。这是一项新发现，可能为对硫磷毒性提供第一个重大洞察。这项研究工作将检验中心假设，即有可能在大鼠身上建立动物模型来评估对硫磷的毒性，并使用该模型来研究毒性机制，然后可以有针对性地开发中和药物来逆转这些机制，防止发病率和死亡率。我们将通过以下具体目标来验证这一假设：目标1：建立大鼠对硫磷中毒模型，并确定预防急性死亡的最佳中和剂。目的2：研究对硫磷暴露对细胞内钙平台发育的影响。目的：确定对硫磷染毒后给予CICR抑制剂能否阻止对硫磷染毒动物模型中钙平台的形成。目的4：确定对硫磷暴露后给予CICR抑制剂是否能防止暴露后神经元的丢失。目的5：确定对硫磷暴露后给予完整动物CICR抑制剂是否能预防对硫磷暴露后认知损害和AE的发生。初步结果证明了这些研究的可行性。这些新的发现为了解对硫磷中毒的原因开辟了一个新的研究领域。这项工作将极有可能对我们理解对硫磷中毒的原因以及我们针对特定分子机制预防与对硫磷接触相关的严重死亡和发病率的能力产生持续而有力的影响。

DESCRIPTION (provided by applicant): Parathion organophosphate pesticides have been identified by the NINDS CounterACT Program as one of the highest priority chemical threats for civilians. Acute parathion exposure can cause death, severe seizures, brain injury, cognitive deficits and epilepsy and is a major risk for intentional use by terrorist groups for mass civilian exposure. Intentional contamination of food and water sources and high rise buildings represent a major threat for catastrophic terrorist attacks. This research proposal will have a significant impact on preventing mortality and morbidity from parathion exposure and will open a new horizon in our ability to understand the molecular mechanisms that mediate parathion toxicity. We propose to develop the first survival model in the rat for acute parathion toxicity and use this model to develop treatments to prevent mortality and morbidity. The BREAKTHROUGH for this project is the discovery using this parathion survival model of a molecular mechanism that potentially mediates many of the severe effects of parathion toxicity. We have discovered that parathion toxicity causes a long lasting increase in hippocampal neuronal calcium (Ca2+) induced Ca2+ release (CICR) from the endoplasmic reticulum in neurons and that this molecular alteration causes a Ca2+ plateau to develop in hippocampal neurons for more than a week after exposure. We propose to demonstrate that this altered Ca2+ signal underlies many of the morbidities of parathion exposure. This is a new discovery and potentially provides the first major insight into parathion toxicity. This research effort will test the CENTRAL HYPOTHESIS that it is possible to develop an animal model in the rat to evaluate parathion toxicity and to use this model to investigate mechanisms of toxicity that can then be targeted to develop CounterACT agents to reverse these mechanisms and prevent morbidity and mortality. We will test this hypothesis by conducting the following Specific Aims: Aim 1: Develop a model for parathion poisoning in the rat and determine the best CounterACT agents to prevent acute mortality. Aim 2: Determine the effect of parathion exposure on the development of the Ca2+ plateau. Aim 3: Determine whether administering inhibitors of CICR to intact animals after parathion exposure can prevent the development of the Ca2+ plateau in the intact animal model of parathion exposure. Aim 4: Determine whether administering inhibitors of CICR to intact animals after parathion exposure can prevent neuronal loss after exposure. Aim 5: Determine whether administering inhibitors of CICR to intact animals after parathion exposure can prevent cognitive impairment and the development of AE after parathion exposure. The preliminary results demonstrate the feasibility of these studies. These novel findings have opened a new frontier for research in understanding the causes of parathion toxicity. This work will have a high probability of having a sustained and powerful impact on our understanding of the cause of parathion toxicity and on our ability to target specific molecular mechanisms to prevent the severe mortality and morbidity associate with parathion exposure.