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: 8829887
• 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/8829887
• 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; 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; cardiovascular visualization; career development; improved; in vitro Model; in vivo; interest; mitochondrial dysfunction; mitochondrial permeability transition pore; mouse model; natural hypothermia; overexpression; oxidant stress; programs; protective effect; targeted imaging; 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.

项目概述/摘要：研究和医师-科学家培训旨在模拟心脏骤停复苏后致死性心脏再灌注损伤的体外和体内机制，以及治疗性低温（TH）对这种损伤的心脏保护。申请人最近对小鼠心脏骤停和小鼠心肌细胞缺血/再灌注（IR）损伤模型的研究表明，在复苏后几分钟内快速、早期冷却可以防止线粒体氧化损伤并保持收缩功能。这两种互补模型中的TH心脏保护与Akt1激活有关。最后，心肌细胞似乎在几分钟内通过Akt定位到线粒体亚细胞部分来适应氧化应激。该建议的中心假设是心脏骤停后TH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。拟议的目标和候选人的职业发展计划将有助于确定：目标#1)心肌细胞I/R期间Akt1激活对于TH保护线粒体完整性是必要的，并且与Akt亚细胞定位、GSK-32抑制和己糖激酶II激活有关；Aim #2)核靶向与线粒体靶向Akt1的过表达将增强或复制TH心脏保护；在心脏骤停小鼠模型中，Akt1磷酸化和亚细胞信号变化也需要TH心脏保护。拟议的工作是夏普博士在心脏细胞生物学和急诊医学方面的先验背景的自然发展，并将为他提供线粒体功能和氧化应激测量，共聚焦成像，靶向转染策略以及体内和体外方法研究心肌I/R损伤的几个新工具。该计划将确保从初级教师成功过渡到独立资助的终身教职。这项提案涉及一个重大的公共卫生问题，该问题是美国的一个主要死亡原因，每年约有335 000人受到影响。非裔美国人的心脏骤停率高得不成比例，在年轻女性中也在上升。尽管前景光明，但在心肺复苏（CPR）期间，特别是在院外环境中，有效和快速地实施TH在技术上具有挑战性。了解akt介导的改善TH患者心血管功能和生存的途径，可能会导致复制或增强TH保护作用的药物辅助剂的发展。

项目成果

Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.

• DOI: 10.1161/circresaha.111.300285
• 发表时间: 2013-03-01
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Hong Z;Kutty S;Toth PT;Marsboom G;Hammel JM;Chamberlain C;Ryan JJ;Zhang HJ;Sharp WW;Morrow E;Trivedi K;Weir EK;Archer SL
• 通讯作者: Archer SL

Dynamin-related protein 1 as a therapeutic target in cardiac arrest.

• DOI: 10.1007/s00109-015-1257-3
• 发表时间: 2015-03
• 期刊: JOURNAL OF MOLECULAR MEDICINE-JMM
• 影响因子: 4.7
• 作者: Sharp, Willard W.