Endothelial Ca2+ signals and vasodilatory function after traumatic brain injury
脑外伤后内皮 Ca2 信号和血管舒张功能
基本信息
- 批准号:8165250
- 负责人:
- 金额:$ 11.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:Accident and Emergency departmentAccountingAcetylcholineAcuteAcute Brain InjuriesAffectAnimal ModelAnimalsArteriesAthleticAttenuatedBiologyBlood PressureBlood VesselsBostonBrainBrain ConcussionBrain InjuriesCalciumCalcium SignalingCaliberCardiologyCardiovascular PhysiologyCardiovascular systemCell membraneClinicalColoradoCytoplasmDataDepartment of DefenseDevelopmentDoctor of PhilosophyEmergency MedicineEndoplasmic ReticulumEndothelial CellsEndotheliumEnvironmentExhibitsFunctional disorderFundingGoalsHypertensionImageIn VitroInjuryInositolIon ChannelKnowledgeLaboratoriesLeadLinkManufactured footballMeasurementMeasuresMediatingMedicalMembraneMembrane PotentialsMentorsMentorshipMesenteric ArteriesMethodsMichiganModelingMolecularMorbidity - disease rateNeurologicNitric OxideNitric Oxide DonorsOperative Surgical ProceduresOutcomePathway interactionsPatientsPhysiologyPostdoctoral FellowPotassium ChannelProductionProgram DevelopmentPublic HealthPulsarReactive Oxygen SpeciesRelative (related person)ReportingResearchResearch PersonnelResearch Project GrantsResidenciesResistanceRodentScientistSignal TransductionSmooth MuscleSmooth Muscle MyocytesSpeedStrokeSubarachnoid HemorrhageSuperoxidesSurvivorsSympathetic Nervous SystemTechniquesTrainingTraining ProgramsTraumaTraumatic Brain InjuryUniversitiesVascular EndotheliumVascular Smooth MuscleVasodilationVermontVisitbasecareercerebrovascularchannel blockerscollegeexpectationexperienceextracellularfluid percussion injurygraduate studenthuman NOS3 proteinimprovedin vivointerestmortalitynerve injurynew therapeutic targetnovelprofessorreceptorresponseskillstempoltetrahydrobiopterintherapeutic targettherapy designtransmission processvasoconstriction
项目摘要
DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in trauma physiology. The Candidate has a background in physiology research (University of Michigan) and has already completed a Medical Scientist Training Program (University of Colorado), with doctoral training in molecular cardiology under the mentorship of Dr. Leslie Leinwand. He also completed residency training in Emergency Medicine (Boston University) and came to the University of Vermont as Research Assistant Professor of Surgery with his own laboratory and startup funding. He now combines his strength in cardiovascular physiology with his clinical experience with traumatic brain injury (TBI), to create a novel and highly translational proposal involving the connections between acute neural injury and vascular function. Traumatic brain injury is a major public health problem, with limited options for medical management of those patients who survive the initial injury. Cardioprotective strategies have been proposed to mediate effects of sympathetic activation after TBI. However, limited understanding of the basic mechanisms linking brain injury to hypertension and changes in vascular function present a critical barrier to progress. The goal of this project is to understand fundamental mechanisms and functional consequences of endothelial vasodilatory signal changes that occur after brain injury. The application includes novel data indicating TBI causes impaired endothelium-dependent vasodilation, despite elevations in endothelial calcium signaling. The hypothesis-driven research project will allow the applicant to develop skill in state-of-the art vascular physiology methods including Ca2+ imaging of intact endothelium, diameter and membrane potential measurements of intact arteries that will provide unprecedented detail into vascular function after acute brain injury. The expected results will lead to a fundamental paradigm shift, changing our understanding of TBI to include not only direct effects on the brain, but also effects on the systemic vasculature that may mediate patient outcomes. The University of Vermont (UVM) is internationally recognized for its strength in vascular biology, particularly Ca2+ signaling and ion channels. Mark Nelson, Ph.D. will mentor the Candidate's scientific development. Dr. Nelson is a recognized leader in the field of vascular biology and has trained numerous postdoctoral fellows and graduate students, many of whom are now established independent investigators. To enhance the training, the program will enlist the expertise of a mentoring committee, including Joseph Brayden, Ph.D., Marilyn Cipolla, PhD, and George Wellman, PhD. Dr. Brayden pioneered the techniques that will be applied in study of vascular smooth muscle membrane potential. Dr. Cipolla has extensive experience in stroke and effects of reactive oxygen species on vascular function, and Dr. Wellman adds expertise in animal models of brain trauma due to subarachnoid hemorrhage. This research environment maximizes the potential for the Candidate to establish a scientific niche from which an academic career can be constructed.
PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) accounts for 1.7 million emergency department visits in the U.S. each year, and groups including the National Collegiate Athletic Association, National Football League, and Department of Defense are particularly interested in concussion and TBI research. This project will elucidate the mechanistic basis and functional consequence of changes in vascular physiology that occur following acute brain injury, a necessary first step in designing therapies to improve clinical outcomes.
描述(由申请者提供):本建议书描述了一项为期5年的创伤生理学学术发展培训计划。应聘者拥有生理学研究背景(密歇根大学),并已完成医学科学家培训计划(科罗拉多大学),在Leslie Leinwand博士的指导下进行了分子心脏病学的博士培训。他还完成了急诊医学(波士顿大学)的住院医师培训,并以自己的实验室和启动资金来到佛蒙特州大学担任外科研究助理教授。他现在将他在心血管生理学方面的优势与他在创伤性脑损伤(TBI)方面的临床经验结合起来,创建了一项涉及急性神经损伤和血管功能之间的联系的新的、高度可翻译的建议。创伤性脑损伤是一个主要的公共卫生问题,对于那些在最初的损伤中幸存下来的患者,医疗处理的选择有限。已经提出了一些心脏保护策略来调节脑外伤后交感神经激活的影响。然而,对脑损伤与高血压和血管功能变化之间的基本机制的了解有限,是取得进展的关键障碍。该项目的目标是了解脑损伤后内皮血管扩张信号变化的基本机制和功能后果。该应用包括新的数据表明,尽管内皮细胞钙信号升高,但脑外伤导致内皮依赖性血管扩张受损。这一假设驱动的研究项目将使申请者掌握最先进的血管生理学方法,包括完整内皮细胞的钙离子成像、完整动脉的直径和膜电位测量,这将为急性脑损伤后的血管功能提供前所未有的细节。预期的结果将导致根本性的范式转变,改变我们对脑损伤的理解,不仅包括对大脑的直接影响,还包括对可能调节患者预后的全身血管系统的影响。佛蒙特州大学(UVM)以其在血管生物学,特别是钙离子信号和离子通道方面的优势而在国际上得到认可。马克·纳尔逊博士将指导候选人的科学发展。纳尔逊博士是血管生物学领域公认的领导者,培养了许多博士后研究员和研究生,其中许多人现在是知名的独立调查人员。为了加强培训,该计划将征集指导委员会的专业知识,包括约瑟夫·布雷登博士、玛丽莲·西波拉博士和乔治·威尔曼博士。布雷登博士开创了将应用于血管平滑肌膜电位研究的技术。西波拉博士在中风和活性氧物质对血管功能的影响方面拥有丰富的经验,威尔曼博士还增加了蛛网膜下腔出血所致脑损伤动物模型方面的专业知识。这种研究环境最大限度地增加了候选人建立一个科学利基的潜力,从这个利基上可以建立一个学术生涯。
公共卫生相关性:在美国,创伤性脑损伤(TBI)每年有170万急诊科就诊,包括国家大学体育协会、国家橄榄球联盟和国防部在内的组织对脑震荡和脑损伤的研究特别感兴趣。该项目将阐明急性脑损伤后血管生理学变化的机制基础和功能后果,这是设计治疗方法以改善临床结果的必要的第一步。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kalev Freeman的其他文献
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{{ truncateString('Kalev Freeman', 18)}}的其他基金
Diversity Supplement to R35 / Endotheliopathy in Trauma
R35/创伤内皮病的多样性补充
- 批准号:
10625207 - 财政年份:2022
- 资助金额:
$ 11.35万 - 项目类别:
Molecular Mechanisms of Histone-Induced Endotheliopathy in Trauma
创伤中组蛋白诱导内皮病的分子机制
- 批准号:
10330739 - 财政年份:2022
- 资助金额:
$ 11.35万 - 项目类别:
Molecular Mechanisms of Histone-Induced Endotheliopathy in Trauma
创伤中组蛋白诱导内皮病的分子机制
- 批准号:
10541883 - 财政年份:2022
- 资助金额:
$ 11.35万 - 项目类别:
Molecular Mechanisms of Histone-Induced Endotheliopathy in Trauma
创伤中组蛋白诱导内皮病的分子机制
- 批准号:
10728375 - 财政年份:2022
- 资助金额:
$ 11.35万 - 项目类别:
Impact of Trauma and its Products on Vascular Endothelial Function
创伤及其产物对血管内皮功能的影响
- 批准号:
9289345 - 财政年份:2017
- 资助金额:
$ 11.35万 - 项目类别:
Impact of Trauma and its Products on Vascular Endothelial Function
创伤及其产物对血管内皮功能的影响
- 批准号:
10224233 - 财政年份:2017
- 资助金额:
$ 11.35万 - 项目类别:
Impact of Trauma and its Products on Vascular Endothelial Function
创伤及其产物对血管内皮功能的影响
- 批准号:
9978883 - 财政年份:2017
- 资助金额:
$ 11.35万 - 项目类别:
Endothelial Ca2+ signals and vasodilatory function after traumatic brain injury
脑外伤后内皮 Ca2 信号和血管舒张功能
- 批准号:
8911334 - 财政年份:2011
- 资助金额:
$ 11.35万 - 项目类别:
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