Endothelial Ca2+ signals and vasodilatory function after traumatic brain injury

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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.