Hypothermia in Cardiac Arrest: Akt Preservation of Mitochondrial Integrity

心脏骤停中的低温：Akt 保护线粒体完整性

• 批准号: 8448186
• 负责人: Willard William Sharp
• 金额: $ 12.66万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448186
• 关键词: Address; Affect; African American; Apoptosis; Biological Preservation; Cardiac; Cardiac Myocytes; Cardiogenic Shock; Cardiopulmonary Resuscitation; Cardiovascular Physiology; Cause of Death; Cell Survival; Cellular biology; Development; Development Plans; Emergency Medicine; Ensure; Erythropoietin; Faculty; Foundations; Functional disorder; Funding; Generations; Genetic; Heart Arrest; Hexokinase 2; Hospitals; Image; In Vitro; Individual; Inhibition of Apoptosis; Injury; Ischemia; K-Series Research Career Programs; Lead; Measures; Mechanics; Mediating; Mentorship; Metabolism; Mitochondria; Modeling; Mus; Myocardial; Myocardium; Nuclear; Outcome; Outer Mitochondrial Membrane; Oxidants; Oxidative Stress; Oxygen; Pathway interactions; Phosphorylation; Phosphotransferases; Physicians; Public Health; Publishing; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Scientist; Signal Transduction; Sirolimus; Solid; Stream; Subcellular Fractions; Techniques; Therapeutic; Training; Training Technics; Transfection; United States; Work; abstracting; career development; heart metabolism; improved; in vitro Model; in vivo; interest; mitochondrial dysfunction; mitochondrial permeability transition pore; mouse model; natural hypothermia; overexpression; oxidant stress; programs; protective effect; tool; young woman

DESCRIPTION (provided by applicant): Project Summary/Abstract Studies and physician-scientist training are proposed to model in vitro and in vivo mechanisms of lethal cardiac reperfusion injury following cardiac arrest resuscitation and therapeutic hypothermia (TH) cardiac protection against this injury. Recent work by the applicant involving mouse cardiac arrest and mouse cardiomyocyte models of ischemia/reperfusion (IR) injury suggests that rapid, early cooling within minutes of resuscitation protects against mitochondrial oxidant injury and preserves contractile function. TH cardioprotection in both these complementary models is associated with Akt1 activation. Finally, cardiomyocytes appear to adapt to oxidant stress within minutes by localization of Akt to the mitochondrial subcellular fraction. The central hypothesis of this proposal is that TH cardioprotection following cardiac arrest is the result of Akt activation and localization to the mitochondria with subsequent inhibition of GSK-32 and activation of hexokinase II. The proposed aims and candidate career development plan will help determine whether: Aim #1) Akt1 activation during cardimyocyte I/R is necessary for TH protection of mitochondrial integrity and is associated with Akt subcellular localization, GSK-32 inhibition and hexokinase II activation; that Aim #2) Overexpression of nuclear versus mitochondrial targeted Akt1 will enhance or replicate TH cardioprotection; and Aim #3) Akt1 phosphorylation and subcellular signaling changes seen in Aims #1 and #2 will also be required for TH cardioprotection in a mouse model of cardiac arrest. The proposed work is a natural progression of Dr Sharp's prior background in cardiac cell biology and training in emergency medicine, and will equip him with several new tools for mitochondrial functional and oxidant stress measures, confocal imaging, targeted transfection strategies, and in vivo as well as in vitro approaches to studies of myocardial I/R injury. The plan will ensure a successful transition from junior faculty to tenure track with independent funding. This proposal addresses a major public health problem that constitutes a leading cause of death in the United States, affecting an estimated 335,000 individuals every year. Rates of cardiac arrest are disproportionately high among African Americans and are rising among young women. Although promising, the effective and rapid implementation of TH during cardiopulmonary resuscitation (CPR) particularly in the out of hospital setting is technically challenging. Understanding the Akt-mediated pathways that improve cardiovascular function and survival with TH could lead to the development of pharmacologic adjuncts that replicate or enhance the protective effects of TH.

描述（由申请人提供）：提出了项目摘要/摘要研究和医师科学家培训，以模拟心脏骤停复苏和治疗性体温过低（TH）心脏防护性损伤后的体外和体内机制。涉及小鼠心脏骤停和小鼠心肌细胞模型的申请人的最新工作表明，在复苏后的几分钟内快速，早冷却可以预防线粒体氧化剂损伤，并保留收缩功能。这两个互补模型中的TH心脏保护都与Akt1激活有关。最后，通过将AKT定位到线粒体亚细胞分数，心肌细胞似乎在几分钟内适应了氧化应激。 该提案的中心假设是心脏骤停后的心脏保护是Akt激活和线粒体定位的结果，随后抑制GSK-32和己糖激酶II的激活。拟议的目标和候选职业发展计划将有助于确定：AIM＃1）在Cardimocyte I/R期间的AKT1激活对于保护线粒体完整性是必要的，并且与AKT亚细胞定位，GSK-32抑制和己糖酶II激活相关；目的＃2）核与线粒体靶向AKT1的过表达将增强或复制心脏保护； AIM＃3）AKT1磷酸化和亚细胞信号传导变化在AIMS＃1和2中所见，也需要在心脏骤停的小鼠模型中进行TH心脏保护。拟议的工作是Sharp博士先前在心脏细胞生物学和急诊医学培训中的背景的自然发展，并将为他提供几种新的工具，用于线粒体功能和氧化剂应力测量，共聚焦成像，靶向转染策略以及体内以及体内以及在体外的研究以及在体外方法的心肌I/R损伤研究。该计划将确保通过独立资助从初级教师到终身轨道的成功过渡。 该提案解决了一个重大的公共卫生问题，该问题构成了美国的主要死亡原因，每年估计有335,000名个人。在非洲裔美国人中，心脏骤停的速度不成比例高，年轻女性的速度正在上升。尽管很有希望，但在心肺复苏（CPR）期间，TH的有效和快速实施在技术上是具有挑战性的。了解改善心血管功能和TH存活的AKT介导的途径可能会导致复制或增强TH保护作用的药理辅助术的发展。