PARATHION EXPOSURE: MECHANISMS OF TOXICTY AND TREATMENT

描述（由申请人提供）：对硫磷有机磷农药已被NINDS CounterACT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，并且是恐怖组织故意使用对硫磷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层建筑是灾难性恐怖袭击的主要威胁。这项研究提案将对预防暴露于氯离子的死亡率和发病率产生重大影响，并将为我们了解介导氯离子毒性的分子机制开辟新的视野。我们建议在大鼠中建立第一个急性胆固醇中毒的存活模型，并使用该模型来开发预防死亡和发病的治疗方法。该项目的突破是使用这种磷离子存活模型发现了一种分子机制，这种机制可能介导磷离子毒性的许多严重影响。我们已经发现，去离子毒性导致海马神经元钙（Ca 2+）诱导的Ca 2+释放（CICR）从神经元内质网的长期持续增加，这种分子改变导致海马神经元中的Ca 2+平台期在暴露后超过一周。我们建议证明，这种改变的Ca2+信号的基础上的许多发病率的暴露。这是一个新的发现，并可能提供了第一个重大的洞察力，以了解磷的毒性。这项研究工作将测试中心假设，即有可能在大鼠中开发一种动物模型来评估氯吡格雷的毒性，并使用该模型来研究毒性机制，然后可以有针对性地开发CounterACT药物来逆转这些机制并预防发病率和死亡率。我们将通过进行以下具体目标来检验这一假设：目标1：建立大鼠中氯吡格雷中毒的模型，并确定预防急性死亡的最佳CounterACT药物。目的2：确定钙离子暴露对Ca2+平台发展的影响。目标3：确定在暴露于氯离子后对完整动物给予CICR抑制剂是否可以防止氯离子暴露的完整动物模型中出现Ca2+平台。目的4：确定是否给予CICR的抑制剂，以完整的动物暴露后，暴露后，可以防止神经元的损失。目标5：确定在暴露于氯吡格雷后，对完整动物给予CICR抑制剂是否可以预防氯吡格雷暴露后的认知障碍和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氯离子毒性的原因开辟了一个新的研究领域。这项工作将有很大的可能性，对我们的理解的原因，磷中毒和我们的能力，以目标特定的分子机制，以防止严重的死亡率和发病率与磷暴露产生持续和强大的影响。

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.