Excitotoxicity and Mitochondrial Dysfunction in Circulatory Arrest- Brain Injury

项目概要/摘要 这项应用建立在我们实验室的开创性工作的基础上，该工作描绘了 低温停循环脑损伤转化模型中的兴奋性毒性和神经炎症 (HCA)这与目前在接受复杂心脏和主动脉手术的患者中使用的技术直接相关， 手术我们建议测试这些机制，特别是N-甲基-D-天冬氨酸（NMDA）拮抗作用， 氯胺酮和线粒体腺苷三磷酸钾（KATP）激活与二氮嗪，使用靶向 在我们的翻译HCA模型中用树枝状聚合物缀合递送， 灌注。在复杂的主动脉手术中，使用此类药物延长安全HCA时间将显着 减少神经损伤并改善这些患者的预后。 通过识别损伤的潜在机制并在临床前大型动物模型中对其进行测试， 本申请中提出的工作将推进该领域，因为目前没有可用的药理学 已在随机试验中证明可显著改善目前使用的药物 体温过低我们的目的是：1）确定NMDA受体拮抗剂氯胺酮是否是一种 在犬模型中低温停循环过程中神经保护剂，2）为了确定 低温停循环时线粒体损伤及线粒体KATP通道的作用 开放剂作为犬模型中的神经保护剂，以及3）评估靶向神经保护策略， 顺行脑灌注低温停循环模型 我们的多学科团队包括一名执业心脏外科医生，他经历了当前的挑战 当进行复杂的主动脉手术时，专门研究脑损伤和线粒体的执业神经科医生 压力，一位专门研究脑损伤的执业神经外科医生，一位专门研究脑损伤的神经科学家 以及神经修复和小胶质细胞激活的机制，纳米医学中心的联合主任， 在树枝状聚合物-药物纳米器件方面的专业知识，用于靶向治疗以减轻神经炎症， 神经病理学家，专门研究神经细胞死亡和线粒体病理生物学。我们共同拥有 将我们的发现转化为临床实践的独特能力。 拟议的实验提供了一个全面的方法来理解的机制， 低温循环停止导致的神经损伤获得的知识可能会带来益处 对于任何需要心脏手术的心血管疾病患者，心脏手术仍然是男性的头号杀手， 美国的女性。

Project Summary / Abstract This application builds on our laboratory's pioneering work delineating critical neurochemical mechanisms of excitotoxicity and neuroinflammation in a translational model of brain injury from hypothermic circulatory arrest (HCA) that is directly relevant to the techniques currently used in patients undergoing complex heart and aortic surgery. We propose to test these mechanisms, specifically N-methyl-D-aspartate (NMDA) antagonism with ketamine and mitochondrial adenosine triphosphate potassium (KATP) activation with diazoxide, using targeted delivery with dendrimer conjugation in our translational HCA model with the addition of antegrade cerebral perfusion. Prolongation of the safe HCA time during complex aortic surgery with such agents will dramatically reduce neurological injury and improve outcomes in these patients. By identifying the underlying mechanisms of injury and testing them in a pre-clinical large animal model, the work proposed in this application will advance the field because there are no currently available pharmacologic agents that have been proven in randomized trials to provide significant improvement to the current use of hypothermia. We propose the following aims: 1) To determine if the NMDA receptor antagonist ketamine is a neuroprotectant during hypothermic circulatory arrest in a canine model, 2) To determine the mechanisms of mitochondrial injury during hypothermic circulatory arrest and the effectiveness of mitochondrial KATP channel openers as neuroprotective agents in a canine model, and 3) To evaluate targeted neuroprotective strategies in a hypothermic circulatory arrest model with antegrade cerebral perfusion (ACP) Our multidisciplinary team includes a practicing cardiac surgeon who experiences the current challenges when performing complex aortic surgery, a practicing neurologist specializing in brain injury and mitochondrial stress, a practicing neurosurgeon who specializes in brain injury, a neuroscientist with expertise in brain injury and mechanisms of neurorepair and microglial activation, the co-director of the Center for Nanomedicine with expertise in dendrimer-drug nanodevices for targeted therapy to attenuate neuroinflammation, and a neuropathologist that specializes in neural cell death and mitochondrial pathobiology. Together we possess the unique ability to translate our findings to clinical practice. The proposed experiments provide a comprehensive approach to understanding the mechanisms of neurological injury due to hypothermic circulatory arrest. The knowledge gained could potentially provide benefit for any patient with cardiovascular disease who requires cardiac surgery, which remains the #1 killer of men and women in the United States.