Pharmacological Induced Torpor/Hypothermia As A Novel Therapy for Improving Post Cardiac Arrest Resuscitation Outcomes

摘要 在心脏病发作和中风后，由于缺氧和营养缺乏造成的细胞损伤(缺血性损伤)。 是导致死亡和残疾的主要原因。冷却(低温)患者以减缓新陈代谢和限制 在心脏手术和后续手术中，细胞缺血损伤是为了保护心脏和大脑。 心脏骤停。诱导体温过低在生理上是困难和耗时的，尤其是在紧急情况下 在这种情况下，对其更广泛的使用造成障碍。此外，还有大量需要优化时机和 低温对细胞保护的深度，同时研究低温保护机制 来自损伤的细胞。该项目试图通过测试一种在 冬眠动物的血液流动，在几分钟内导致麻木(代谢不足/体温过低)。 具体地说，这个项目测试了这样一种假设，即通过药物诱导昏迷/低温 5‘-腺苷一磷酸(AMP)可通过同时激活AMP改善CA术后的预后 激活的激酶(AMPK)，同时抑制线粒体分裂蛋白Dynamin相关蛋白1(Drp1)， 从而通过改善线粒体和代谢功能逆转心肌顿抑。我的初选 数据表明，这种名为5‘AMP的化学物质在几分钟内迅速引起体温过低和心脏保护 行政管理。目的1检测5‘AMP对多种心脏骤停模型心脏骤停结局的影响。 缺血/再灌注损伤，同时优化亚低温条件。目标2测试是否影响 5‘AMP是由AMPK通过利用基因减弱或过表达AMPK的小鼠来介导的。 最后，Aim 3确定Drp1的表达是否对心脏骤停后线粒体和 心肌功能不全。这项研究的成功将建立一种快速诱导低温的新方法 同时确定AMPK和Drp1为心脏骤停和缺血性损伤后的新治疗靶点。

ABSTRACT Cellular injury from oxygen and nutrient deprivation (ischemic injury) occurs following heart attacks and strokes and is a major cause of death and disability. Cooling (hypothermia) patients to slow metabolism and limit cellular injury from ischemic injury is done to protect the heart and brain in cardiac surgery and following cardiac arrest. Inducing hypothermia is physically difficult and time consuming particularly in emergent situations, creating a barrier to its broader use. In addition, there is a large need to optimize the timing and depth of hypothermia for cellular protection while investigating the mechanisms of how hypothermia protects cells from injury. This project attempts to overcome these barriers by testing a novel chemical found in the blood stream of hibernating animals that induces torpor (hypo-metabolism/hypothermia) within minutes. Specifically, this project tests the hypothesis that pharmacological induction of torpor/hypothermia with 5’adenosine monophosphate (AMP) will improve post-CA outcomes by simultaneously activating AMP activated kinase (AMPK), while inhibiting the mitochondrial fission protein Dynamin related protein 1 (Drp1), thereby reversing myocardial stunning through improved mitochondrial and metabolic function. My preliminary data demonstrate that this chemical, 5’AMP rapidly induces hypothermia and cardioprotection within minutes of administration. Aim 1 tests the effects of 5’AMP on improving cardiac arrest outcomes in multiple models of ischemia/reperfusion injury, while optimizing the conditions of hypothermia. Aim 2 tests whether the effects of 5’AMP are mediated by AMPK through the use of mice with genetically attenuated or overexpressing AMPK. Finally, Aim 3 determines whether Drp1 expression is necessary for post-cardiac arrest mitochondrial and myocardial dysfunction. Success of this research will establish a new method for rapidly inducing hypothermia while identifying AMPK and Drp1 as new therapeutic targets for post cardiac arrest and ischemic injury.