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：
8499378
负责人：
Kalev Freeman
金额：
$ 11.35万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
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：
https://reporter.nih.gov/project-details/8499378
关键词：
Accident and Emergency department Accounting Acetylcholine Acute Acute Brain Injuries Affect Animal Model Animals Arteries Athletic Attenuated Biology Blood Pressure Blood Vessels Boston Brain Brain Concussion Brain Injuries Calcium Calcium Signaling Caliber Cardiology Cardiovascular Physiology Cardiovascular system Cell membrane Clinical Colorado Cytoplasm Data Department of Defense Development Doctor of Philosophy Emergency Medicine Endoplasmic Reticulum Endothelial Cells Endothelium Environment Exhibits Functional disorder Funding Goals Hypertension Image In Vitro Injury Inositol Ion Channel Knowledge Laboratories Lead Link Manufactured football Measurement Measures Mediating Medical Membrane Membrane Potentials Mentors Mentorship Mesenteric Arteries Methods Michigan Modeling Molecular Morbidity - disease rate Neurologic Nitric Oxide Nitric Oxide Donors Operative Surgical Procedures Outcome Pathway interactions Patients Physiology Postdoctoral Fellow Potassium Channel Production Program Development Public Health Pulsar Reactive Oxygen Species Relative (related person)Reporting Research Research Personnel Research Project Grants Residencies Resistance Rodent Scientist Signal Transduction Smooth Muscle Smooth Muscle Myocytes Speed Stroke Subarachnoid Hemorrhage Superoxides Survivors Sympathetic Nervous System Techniques Training Training Programs Trauma Traumatic Brain Injury Universities Vascular Endothelium Vascular Smooth Muscle Vasodilation Vermont Visit base career cerebrovascular channel blockers college expectation experience extracellular fluid percussion injury graduate student human NOS3 protein improved in vivo interest mortality nerve injury new therapeutic target novel professor receptor response skills tempol tetrahydrobiopterin therapeutic target therapy design transmission process vasoconstriction

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.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，以开发创伤生理学的学术生涯。候选人具有生理学研究背景（密歇根大学），并且已经完成了医学科学家培训计划（科罗拉多大学），并在Leslie Leinwand博士的指导下接受了分子心脏病学博士学位培训。他还完成了急诊医学（波士顿大学）的住院医师培训，并通过自己的实验室和初创企业来到佛蒙特大学，担任研究助理教授。现在，他将心血管生理学的力量与创伤性脑损伤（TBI）的临床经验相结合，以创建一种新颖且高度转化的建议，涉及急性神经损伤与血管功能之间的联系。创伤性脑损伤是一个主要的公共卫生问题，对于那些在最初受伤中生存的患者的医疗管理方案有限。已经提出了心脏保护策略来介导TBI后交感神经激活的影响。然而，对将脑损伤与高血压和血管功能变化联系起来的基本机制的理解有限，这是进步的关键障碍。该项目的目的是了解脑损伤后发生的内皮血管舒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TBI导致内皮依赖性血管舒张受损，尽管内皮钙信号传导升高。假设驱动的研究项目将使申请人能够开发出最先进的血管生理方法的技能，包括完整内皮，直径和膜的完整动脉的膜潜在测量的成像，这些动脉将在急性脑损伤后将细节提供为血管功能的前所未有的细节。预期的结果将导致基本的范式转移，改变我们对TBI的理解不仅包括对大脑的直接影响，而且还对可能介导患者结果的系统性脉管系统产生影响。佛蒙特大学（UVM）因其在血管生物学方面的强度，尤其是CA2+信号传导和离子通道而受到国际认可。马克·尼尔森（Mark Nelson）博士将指导候选人的科学发展。尼尔森博士是血管生物学领域的公认领导者，并培训了许多博士后研究员和研究生，其中许多人现在是成立的独立研究人员。为了增强培训，该计划将获得指导委员会的专业知识，包括Joseph Brayden博士，玛丽莲·奇波拉（Marilyn Cipolla）博士和博士。 Brayden博士开创了将用于研究血管平滑肌膜电位的技术。 Cipolla博士在中风和活性氧对血管功能的影响方面具有丰富的经验，Wellman博士在蛛网膜下腔出血引起的动物创伤动物模型中增加了专业知识。这种研究环境最大程度地提高了候选人建立科学利基市场的潜力，可以从中建立学术职业。