Hypothermia for Cardiac Arrest: Optimizing Akt-Nitric Oxide Synthase Signaling
低温治疗心脏骤停:优化 Akt-一氧化氮合酶信号转导
基本信息
- 批准号:8294612
- 负责人:
- 金额:$ 12.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-08-20 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAnimal ExperimentsAnimalsAttenuatedBioavailableBiologyBiomedical EngineeringBlood CirculationBrainCardiacCardiac MyocytesCardiogenic ShockCardiopulmonary ResuscitationCardiovascular PhysiologyCardiovascular systemCaringCell DeathCell modelCessation of lifeChicagoClinicalCommunitiesDataDevelopmentDiseaseElectron Spin Resonance SpectroscopyEmergency MedicineEmergency SituationEnzyme ActivationEquilibriumFamilyFamily suidaeFluorescent ProbesFolateFree RadicalsFunctional disorderGenerationsHealedHeartHeart ArrestHospitalsHourHumanInjuryInstitutesInsulinIschemiaIsomerismKnock-outLaboratoriesLaboratory miceMeasuresMechanicsMediatingMedicineMentorsMentorshipMitochondriaModelingMolecularMolecular BiologyMusMyocardialMyocardial dysfunctionNG-Nitroarginine Methyl EsterNOS1 geneNOS3 geneNervous System PhysiologyNervous System TraumaNeurological outcomeNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IOutcomeOxidantsOxidasesPathway interactionsPatientsPharmaceutical PreparationsPharmacologic SubstancePhasePhosphorylationPhysiciansPrincipal InvestigatorProcessProductionProtein IsoformsProtein KinaseQuality of lifeReactive Nitrogen SpeciesReactive Oxygen SpeciesRefractoryRelative (related person)Reperfusion InjuryReperfusion TherapyResearchResearch PersonnelResuscitationRoleScientistSeriesSignal PathwaySignal TransductionSourceSuperoxide DismutaseSuperoxidesSyndromeTemperatureTestingTherapeuticTherapeutic InterventionThreonineTimeTissuesTrainingTraining ProgramsTranslational ResearchUniversitiesWorkXanthine Dehydrogenaseaortic balloon pumparginine methyl esterbasecardiovascular injurycareer developmentcofactordesignexperiencehealinghuman NOS3 proteinimprovedin vitro Modelin vivoindexinginhibitor/antagonistinnovationinterestmembermortalitymouse modelmovienatural hypothermianoveloxidant stressoxidationpreventprogramsprotective effectskillstetrahydrobiopterintherapy developmentvasoactive agent
项目摘要
DESCRIPTION (provided by applicant): This proposal is a natural extension of the candidate's background in Emergency Medicine and Biomedical Engineering. His unique background and passion for translational science has already contributed to animal resuscitation research. This innovative work models early post-cardiac arrest reperfusion injury in our patients, i.e. cardiovascular collapse despite initial return of spontaneous circulation (ROSC). The training program will enhance the mouse modeling already done by formally training the applicant in the best molecular biology approaches for study of nitric oxide signaling and uncoupling. The applicant will benefit from multi-disciplinary mentorship within the Emergency Resuscitation Center, building upon expertise in heart oxidant injury and adaptation, and free radical biology. The sponsors Drs. Vanden Hoek and McNally are experienced physician-scientists. They are also collaborators interested in oxidantmediated heart contractile dysfunction and death in cardiomyocyte and mouse models. This Career Development Project builds upon the strengths of the applicant, the training program and institutional support and mentorship. We hypothesize that protective hypothermia following cardiac arrest increases Akt-related constitutive nitric oxide synthase (cNOS) NO-signaling, while attenuating cNOS uncoupling and generation of damaging reactive oxygen species (ROS). Specifically, in a mouse model of cardiac arrest we will: (Aim 1) Optimize the target temperature of protective hypothermia based on heart Akt and cNOS activity; (Aim 2) Test the relative importance of NOS1/NOS3 in post-cardiac arrest injury, NO and ROS generation, and hypothermia protection using selective-inhibitor and knockout strategies; and (Aim 3). Test whether hypothermia protection can be reproduced by NOS substrate/cofactor repletion strategies. The University of Chicago Department of Medicine and Section of Emergency Medicine have a track-record of successful mentoring using the K08 physician-scientist training program. The proposed training will provide Dr. Beiser with additional skills to become a leading independent physician-scientist in his field. From a layperson perspective, cardiac arrest (when the heart stops) is different than depicted on TV or the movies-most people initially resuscitated do not survive. This work will help understand how cooling the body a few degrees can actually increase a type of oxidant stress that helps the body heal itself.
描述(由申请人提供):该提案是候选人急诊医学和生物医学工程背景的自然延伸。他独特的背景和对转化科学的热情已经为动物复苏研究做出了贡献。这项创新工作模拟了我们患者的早期心脏骤停后再灌注损伤,即尽管最初恢复了自主循环(ROSC),但心血管崩溃。该培训计划将通过正式培训申请人用于研究一氧化氮信号传导和解偶联的最佳分子生物学方法来增强已经完成的小鼠建模。申请人将受益于紧急复苏中心内基于心脏氧化损伤和适应以及自由基生物学方面的专业知识的多学科指导。赞助商博士。范登·霍克和麦克纳利是经验丰富的医师科学家。他们也是对心肌细胞和小鼠模型中氧化剂介导的心脏收缩功能障碍和死亡感兴趣的合作者。该职业发展项目建立在申请人的优势、培训计划以及机构支持和指导的基础上。我们假设心脏骤停后的保护性低温会增加 Akt 相关的组成型一氧化氮合酶 (cNOS) NO 信号传导,同时减弱 cNOS 解偶联和破坏性活性氧 (ROS) 的产生。具体来说,在心脏骤停的小鼠模型中,我们将:(目标1)根据心脏Akt和cNOS活性优化保护性低温的目标温度; (目标 2)使用选择性抑制剂和敲除策略测试 NOS1/NOS3 在心脏骤停后损伤、NO 和 ROS 生成以及低温保护中的相对重要性;和(目标 3)。测试 NOS 底物/辅因子补充策略是否可以重现低温保护。芝加哥大学医学系和急诊医学科拥有使用 K08 医师科学家培训计划进行成功指导的记录。拟议的培训将为 Beiser 博士提供额外的技能,使其成为其领域内领先的独立医师科学家。从外行人的角度来看,心脏骤停(心脏停止跳动时)与电视或电影中描述的不同——大多数最初复苏的人都无法存活。这项工作将有助于了解如何将身体冷却几度实际上会增加一种有助于身体自我修复的氧化应激。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The emergency cardiac arrest response team (eCART): a novel strategy for improving therapeutic hypothermia utilization following out-of-hospital cardiac arrest.
紧急心脏骤停反应小组 (eCART):一种改善院外心脏骤停后低温治疗利用率的新策略。
- DOI:10.1016/j.resuscitation.2014.10.006
- 发表时间:2014
- 期刊:
- 影响因子:6.5
- 作者:Deal,NathanS;Sharp,WillardW;Orbelyan,GerasimA;Borak,MeredithH;Friant,Janet;Shah,AtmanP;Beiser,DavidG
- 通讯作者:Beiser,DavidG
Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.
- DOI:10.1097/ccm.0000000000000817
- 发表时间:2015-02
- 期刊:
- 影响因子:8.8
- 作者:Sharp WW;Beiser DG;Fang YH;Han M;Piao L;Varughese J;Archer SL
- 通讯作者:Archer SL
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David Gustav Beiser其他文献
David Gustav Beiser的其他文献
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{{ truncateString('David Gustav Beiser', 18)}}的其他基金
Hypothermia for Cardiac Arrest: Optimizing Akt-Nitric Oxide Synthase Signaling
低温治疗心脏骤停:优化 Akt-一氧化氮合酶信号转导
- 批准号:
7862489 - 财政年份:2008
- 资助金额:
$ 12.42万 - 项目类别:
Hypothermia for Cardiac Arrest: Optimizing Akt-Nitric Oxide Synthase Signaling
低温治疗心脏骤停:优化 Akt-一氧化氮合酶信号转导
- 批准号:
8098021 - 财政年份:2008
- 资助金额:
$ 12.42万 - 项目类别:
Hypothermia for Cardiac Arrest: Optimizing Akt-Nitric Oxide Synthase Signaling
低温治疗心脏骤停:优化 Akt-一氧化氮合酶信号转导
- 批准号:
7676749 - 财政年份:2008
- 资助金额:
$ 12.42万 - 项目类别:
Hypothermia for Cardiac Arrest: Optimizing Akt-Nitric Oxide Synthase Signaling
低温治疗心脏骤停:优化 Akt-一氧化氮合酶信号转导
- 批准号:
7530599 - 财政年份:2008
- 资助金额:
$ 12.42万 - 项目类别:
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