Endothelial Ca2+ signals and vasodilatory function after traumatic brain injury

描述（由申请人提供）：此提案描述了一个为期5年的创伤生理学学术生涯发展培训计划。候选人具有生理学研究背景（密歇根大学），并已完成医学科学家培训计划（科罗拉多大学），并在Leslie Leinwand博士的指导下接受分子心脏病学博士培训。他还完成了急诊医学（波士顿大学）的住院医师培训，并带着自己的实验室和启动资金来到佛蒙特大学担任外科研究助理教授。现在，他将自己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，创造了一个涉及急性神经损伤和血管功能之间联系的新颖且高度可转化的建议。外伤性脑损伤是一个重大的公共卫生问题，对那些最初受伤后幸存下来的患者的医疗管理选择有限。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，对脑损伤与高血压和血管功能改变之间的基本机制的有限理解是进展的关键障碍。该项目的目的是了解脑损伤后内皮血管舒张信号改变的基本机制和功能后果。该应用包括新的数据表明，尽管内皮钙信号升高，创伤性脑损伤导致内皮依赖性血管舒张受损。这个假设驱动的研究项目将允许申请人发展最先进的血管生理学方法的技能，包括完整内皮的Ca2+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，改变我们对创伤性脑损伤的理解，不仅包括对大脑的直接影响，还包括可能介导患者预后的对全身血管系统的影响。佛蒙特大学（UVM）因其在血管生物学方面的实力而享誉国际，特别是Ca2+信号和离子通道。Mark Nelson博士将指导候选人的科学发展。Nelson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，其中许多人现在是独立的研究人员。为了加强培训，该项目将招募一个指导委员会的专家，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。Brayden博士开创了将应用于血管平滑肌膜电位研究的技术。Cipolla博士在中风和活性氧对血管功能的影响方面拥有丰富的经验，Wellman博士在蛛网膜下腔出血引起的脑创伤动物模型方面增加了专业知识。这种研究环境最大限度地提高了候选人建立科学利基的潜力，从而可以构建学术生涯。

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.