Endothelial Ca2+ signals and vasodilatory function after traumatic brain injury

Summary

Principal Investigator: Kalev Freeman
Abstract: 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.
Funding Period: 2011-08-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Cardiac reactive oxygen species after traumatic brain injury
    Brett E Larson
    Department of Surgery, University of Vermont, Burlington, Vermont 05405, USA
    J Surg Res 173:e73-81. 2012
  2. pmc Cellular technology improves transmission success of pre-hospital electrocardiograms
    Nicholas Larochelle
    University of Pittsburgh Emergency Medicine Residency, Pittsburgh, PA, USA
    Am J Emerg Med 31:1564-70. 2013
  3. ncbi Potholes and molehills: bias in the diagnostic performance of diffusion-tensor imaging in concussion
    Richard Watts
    From the Departments of Radiology R W, C G F, J P N, Surgery A T, K V, and Neurology C G F, University of Vermont, Given Medical Building E301, 89 Beaumont Ave, Burlington, VT 05405
    Radiology 272:217-23. 2014

Research Grants

  1. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
  2. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
  3. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
  4. Arterial Smooth Muscle Chloride Channels
    Jonathan H Jaggar; Fiscal Year: 2013
  5. Vascular control by K+ channel trafficking
    Jonathan H Jaggar; Fiscal Year: 2013
  6. TRP Channel-Dependent Regulation of Arterial Tone
    Scott Earley; Fiscal Year: 2013
  7. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
  8. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
  9. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
  10. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013

Detail Information

Publications3

  1. pmc Cardiac reactive oxygen species after traumatic brain injury
    Brett E Larson
    Department of Surgery, University of Vermont, Burlington, Vermont 05405, USA
    J Surg Res 173:e73-81. 2012
    ..We examined blood pressure and left ventricle contractility after TBI, and tested the hypothesis that β-adrenergic blockade would decrease oxidative stress after TBI...
  2. pmc Cellular technology improves transmission success of pre-hospital electrocardiograms
    Nicholas Larochelle
    University of Pittsburgh Emergency Medicine Residency, Pittsburgh, PA, USA
    Am J Emerg Med 31:1564-70. 2013
    ..This study investigated the association between the method of pre-hospital 12-lead ECG transmission (radio transmission vs. cellular phone transmission) and the success of transmission and legibility of 12-lead ECGs in a rural setting...
  3. ncbi Potholes and molehills: bias in the diagnostic performance of diffusion-tensor imaging in concussion
    Richard Watts
    From the Departments of Radiology R W, C G F, J P N, Surgery A T, K V, and Neurology C G F, University of Vermont, Given Medical Building E301, 89 Beaumont Ave, Burlington, VT 05405
    Radiology 272:217-23. 2014
    ....

Research Grants30

  1. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  2. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  3. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
    ..The projects are highly interactive, and all three take full advantage of the proposed cores. ..
  4. Arterial Smooth Muscle Chloride Channels
    Jonathan H Jaggar; Fiscal Year: 2013
    ....
  5. Vascular control by K+ channel trafficking
    Jonathan H Jaggar; Fiscal Year: 2013
    ..This proposal will provide significant novel information concerning cerebral artery contractility regulation by physiological and pathological mechanisms that control BKCa channel surface expression. ..
  6. TRP Channel-Dependent Regulation of Arterial Tone
    Scott Earley; Fiscal Year: 2013
    ..abstract_text> ..
  7. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  8. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  9. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  10. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  11. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  12. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  13. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  14. Pregnancy/NO Induced Changes in UAE Ca2+Signaling
    Ian M Bird; Fiscal Year: 2013
    ..Having more complete knowledge of how cell function is regulated in pregnancy will certainly take us one step closer to overcoming this potentially devastating disease that effects so many in this country and beyond. ..
  15. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  16. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  17. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..