Endothelial Ca2+ signals and vasodilatory function after traumatic brain injury

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，为创伤生理学的学术生涯的发展。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），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，并来到佛蒙特大学担任外科研究助理教授，拥有自己的实验室和启动资金。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）方面的临床经验相结合，创造了一种新颖的高度转化的建议，涉及急性神经损伤和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，对于那些在最初损伤中幸存的患者的医疗管理选择有限。已经提出了脑保护策略来介导TBI后交感神经激活的作用。然而，对脑损伤与高血压和血管功能变化之间联系的基本机制的了解有限，这是进展的关键障碍。本项目的目标是了解脑损伤后内皮血管舒张信号变化的基本机制和功能后果。该申请包括新的数据，表明TBI导致内皮依赖性血管舒张受损，尽管内皮钙信号升高。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，这将提供急性脑损伤后血管功能的前所未有的细节。预期的结果将导致根本的范式转变，改变我们对TBI的理解，不仅包括对大脑的直接影响，还包括对可能介导患者结局的全身血管系统的影响。佛蒙特大学（UVM）因其在血管生物学，特别是Ca2+信号传导和离子通道方面的实力而受到国际认可。Mark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，培养了众多博士后研究员和研究生，其中许多人现在已经成为独立的研究人员。为了加强培训，该计划将争取一个指导委员会的专业知识，包括约瑟夫布雷登，博士，Marilyn Cipolla博士和乔治韦尔曼博士。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拥有专业知识。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.