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

药理学诱导的麻木/低温作为改善心脏骤停后复苏结果的新疗法

基本信息

批准号：
9160849
负责人：
Willard William Sharp
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9160849
关键词：
5&apos -AMP-activated protein kinase Accounting Acute Adenosine Monophosphate Affect Animals Anoxic Encephalopathy Apoptosis Attenuated Basal metabolic rate Biological Preservation Blood Brain Calcium Cardiac Cardiac Surgery procedures Cardiogenic Shock Cardiopulmonary Resuscitation Cause of Death Chemicals Data Dynamin Dynamin I Functional disorder Glucose Glycolysis Health Heart Heart Arrest Hibernation Individual Injury Ischemia Knockout Mice Mammals Mediating Mediator of activation protein Metabolic Metabolism Methods Mitochondria Modeling Molecular Molecular Models Mus Myocardial Myocardial Infarction Myocardial Stunning Myocardial dysfunction Necrosis Nucleotides Operative Surgical Procedures Organelles Outcome Oxygen Pathologic Patients Phosphotransferases Physiological Process Production Protein Kinase Proteins Publishing Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Research Respiration Resuscitation Shock Signal Pathway Stream Stress Stroke Structure Temperature Testing Therapeutic Time Transplantation Uncertainty cell injury disability heart metabolism improved improved outcome induced hypothermia inhibitor/antagonist mitochondrial dysfunction mitochondrial metabolism molecular modeling mortality mouse model natural hypothermia new therapeutic target novel novel strategies novel therapeutics nutrient deprivation overexpression oxidation protective effect success

项目摘要

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.

抽象的心脏病和中风后会发生因氧气和营养缺乏（缺血性损伤）造成的细胞损伤冷却（体温过低）患者的新陈代谢减慢和限制是导致死亡和残疾的主要原因。缺血性损伤造成的细胞损伤是为了在心脏手术及后续手术中保护心脏和大脑引起心脏骤停在身体上是困难且耗时的，尤其是在紧急情况下。情况下，对其更广泛的使用造成了障碍，此外，还迫切需要优化时间和方法。细胞保护的低温深度，同时研究低温保护机制该项目试图通过测试在细胞中发现的一种新型化学物质来克服这些障碍。冬眠动物的血流在几分钟内引起麻木（代谢减退/体温过低）。具体来说，该项目测试了这样的假设：药物诱导麻木/体温过低的假设 5' 腺苷单磷酸 (AMP) 将通过同时激活 AMP 来改善 CA 后的结果激活激酶（AMPK），同时抑制线粒体裂变蛋白Dynamin相关蛋白1（Drp1），通过改善线粒体和代谢功能来逆转心肌顿抑。数据表明，这种化学物质 5'AMP 在数分钟内迅速引起体温降低和心脏保护作用目标 1 测试 5’AMP 在多种心脏骤停模型中改善心脏骤停结果的效果。缺血/再灌注损伤，同时优化低温条件，测试是否有影响。 5'AMP 通过使用 AMPK 基因减弱或过度表达的小鼠来由 AMPK 介导。最后，目标 3 确定 Drp1 表达对于心脏骤停后线粒体和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 作为心脏骤停后和缺血性损伤的新治疗靶点。