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.

抽象的氧气和养分剥夺（缺血性损伤）因心脏病发作和中风而发生的细胞损伤（缺血性损伤）并且是死亡和残疾的主要原因。冷却（体温过低）患者缓慢代谢并限制缺血性损伤的细胞损伤是为了保护心脏手术和随后的心脏和大脑心脏停搏。诱导体温过低，在身体上很困难且耗时，尤其是在紧急情况下情况，为其更广泛的使用造成了障碍。此外，很需要优化时间和在研究低温保护的机制的同时，体温过低的深度用于细胞保护细胞受伤。该项目试图通过测试一种在几分钟之内诱导Torpor（替代代谢/体温过低）的冬眠动物的血液。具体而言，该项目检验了以下假设 5'adenosine Monophate（AMP）将通过简单地激活AMP来改善CA后结局活化的激酶（AMPK），同时抑制线粒体裂变蛋白动力蛋白相关蛋白1（DRP1），从而通过改进的线粒体和代谢功能逆转心肌令人惊叹。我的初步数据表明，这种化学物质5'在行政。 AIM 1测试5'AMP在多种模型中改善心脏骤停结果的影响缺血/再灌注损伤，同时优化了体温过低的状况。 AIM 2测试是否影响 5'AMP通过将小鼠与一般衰减或过表达的AMPK一起使用AMPK介导。最后，AIM 3确定DRP1表达是否需要后心脏骤停线粒体和心肌功能障碍。这项研究的成功将建立一种快速诱导体温过低的新方法同时将AMPK和DRP1识别为心脏骤停和缺血性损伤的新治疗靶标。