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

• 批准号: 9918959
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918959
• 关键词: 5' -AMP-activated protein kinase; Acute; Adenosine Monophosphate; Affect; Animals; Anoxic Encephalopathy; Apoptosis; Attenuated; Basal metabolic rate; Blood; Brain; Calcium; Cardiac; Cardiac Surgery procedures; Cardiogenic Shock; Cardiopulmonary Resuscitation; Cause of Death; Chemicals; Clinical; Consumption; Data; Dynamin; Functional disorder; Glucose; Glycolysis; Health; Heart; Heart Arrest; Heart Mitochondria; Hibernation; Individual; Injury; Ischemia; Knockout Mice; Mammals; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Stunning; Myocardial dysfunction; Necrosis; Nucleotides; Operative Surgical Procedures; Organelles; Outcome; Oxygen; Pathologic; Patients; Pharmacology; 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 Surgery; Uncertainty; cardioprotection; cell injury; disability; genetic manipulation; heart metabolism; improved; improved outcome; induced hypothermia; inhibitor/antagonist; ischemic injury; mitochondrial dysfunction; mitochondrial metabolism; molecular modeling; mortality; mouse model; natural hypothermia; new therapeutic target; novel; novel strategies; novel therapeutics; nutrient deprivation; overexpression; oxidation; preservation; protective effect; rapid technique; success

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.

摘要 心脏病发作和中风后，细胞因缺氧和营养缺乏而受到损伤（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，以减缓新陈代谢并限制 在心脏手术和随后的心脏手术中， 心脏骤停诱导低温是物理困难和耗时的，特别是在紧急情况下 这就为它的广泛使用制造了障碍。此外，还需要优化时间安排， 研究低温如何保护细胞的机制时， 细胞损伤。该项目试图通过测试一种新的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（低代谢/体温过低）。 具体而言，该项目测试了以下假设： 5 '腺苷酸（AMP）将通过同时激活AMP来改善CA后的结果 活化激酶（AMPK），同时抑制线粒体分裂蛋白发动蛋白相关蛋白1（Drp 1）， 从而通过改善线粒体和代谢功能逆转心肌顿抑。我的初步 数据表明，这种化学物质，5 'AMP在几分钟内迅速诱导体温降低和心脏保护作用， 局目的1测试5 'AMP在多种心脏骤停模型中改善心脏骤停结局的作用。 缺血/再灌注损伤，同时优化低温条件。目标2测试是否影响 通过使用具有遗传减毒或过表达AMPK的小鼠，5 'AMP由AMPK介导。 最后，目的3确定Drp 1表达是否是心脏骤停后线粒体和心肌细胞所必需的。 心肌功能障碍本研究的成功将为快速诱导低温建立一种新的方法 同时确定AMPK和Drp 1作为心脏骤停后和缺血性损伤的新治疗靶点。

项目成果

SAEM Response to the National Institutes of Health request for information: Future directions in violence against women research.

SAEM 对美国国立卫生研究院信息请求的回应：暴力侵害妇女行为研究的未来方向。

• DOI: 10.1111/acem.14775
• 发表时间: 2023
• 期刊: Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
• 作者: Stanford,KimberlyA;Macias-Konstantopoulos,Wendy;Linden,Judith;Agrawal,Pooja;Cortes,Emma;Barron,RebeccaJ;Stoklosa,Hanni;Dekker,AnnetteM;Paxton,James;Knack,Sarah;Sharp,WillardW;SAEMResearchCommittee
• 通讯作者: SAEMResearchCommittee

Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest.

• DOI: 10.1371/journal.pone.0185046
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Piao L;Fang YH;Kubler MM;Donnino MW;Sharp WW
• 通讯作者: Sharp WW

Community Response Programs: The Real Question Is "Are They Scalable?".

社区响应计划：真正的问题是“它们可扩展吗？”。

• DOI: 10.1016/j.annemergmed.2023.01.043
• 发表时间: 2023
• 期刊: Annals of emergency medicine
• 影响因子: 6.2
• 作者: Pratt,Abdullah;Tataris,Katie;Sharp,WillardW
• 通讯作者: Sharp,WillardW

Emergency Department-initiated High-flow Nasal Cannula for COVID-19 Respiratory Distress.

• DOI: 10.5811/westjem.2021.3.50116
• 发表时间: 2021-07-20
• 期刊: The western journal of emergency medicine
• 作者: Jarou ZJ;Beiser DG;Sharp WW;Chacko R;Goode D;Rubin DS;Kurian D;Dalton A;Estime SR;O'Connor M;Patel BK;Kress JP;Spiegel TF
• 通讯作者: Spiegel TF

Emergency medicine faculty serving on standing NIH and AHRQ study sections from 2019 to 2020.

2019 年至 2020 年，急诊医学教员在 NIH 和 AHRQ 研究部门任职。

• DOI: 10.1111/acem.14342
• 发表时间: 2022
• 期刊: Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
• 作者: Moore,AndrewB;Puskarich,Mike;Vogel,JodyA;Brown,Jeremy;Sharp,WillardW
• 通讯作者: Sharp,WillardW