Excitotoxicity and Mitochondrial Dysfunction in Circulatory Arrest- Brain Injury

项目摘要/摘要 这一应用建立在我们实验室描绘关键神经化学机制的开创性工作基础上 低温停循环所致脑损伤翻译模型的兴奋性毒性和神经炎症 (HCA)与目前接受复杂心脏和主动脉手术的患者的技术直接相关 做手术。我们建议测试这些机制，特别是N-甲基-D-天冬氨酸(NMDA)的拮抗作用 二氮嗪对氯胺酮和线粒体三磷酸腺苷钾(KATP)的激活作用 在我们的平移型HCA模型中加入顺行脑区的树枝状大分子偶联给药 灌流。在使用这类药物的复杂主动脉手术中延长安全的HCA时间将显著 减少神经损伤，改善这些患者的预后。 通过确定损伤的潜在机制并在临床前的大型动物模型中进行测试， 这项申请中提出的工作将推动该领域的发展，因为目前还没有可用的药理学 已经在随机试验中被证明能够显著改善目前的使用情况的药物 体温过低。我们提出以下目标：1)确定NMDA受体拮抗剂氯胺酮是否是一种 低温停循环犬模型中的神经保护剂，2)确定其作用机制 低温停循环对线粒体的损伤及线粒体KATP通道的作用 在犬模型中作为神经保护剂的开放剂，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的建立 我们的多学科团队包括一名经历了当前挑战的执业心脏外科医生 在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 Stress，一位专门研究脑损伤的执业神经外科医生，一位在脑损伤方面有专长的神经科学家 和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与 在用于靶向治疗以减轻神经炎症的树状大分子药物纳米设备方面的专业知识，以及 专门研究神经细胞死亡和线粒体病理生物学的神经病理学家。我们共同拥有 将我们的发现转化为临床实践的独特能力。 建议的实验提供了一种全面的方法来理解 低温停循环所致的神经损伤。所获得的知识可能会带来潜在的好处 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和 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.