The central theme of this proposal is to identify the metabolic destination of cerebral glucose taken up after traumatic brain injury (TBI), thereby discovering alternative metabolic pathways receptive to interventions (metabolic therapy) to enhance cellular and functional recovery and ultimately change the future of TBI patient management. Two basic science projects will explore these fundamental issues, and are designed to lead as well as complement two clinical projects. Project 1 (Dr. Richard Sutton) addresses the administration of glucose and pyruvate following cortical controlled impact in the rat to examine their impact on cerebral metabolism, cellular protection and outcome. Project 2 (Dr. Mayumi Prins) will study postnatal day 35 and postnatal day 90 rats using the developmental maturation of fuel transporters as an independent variable. Transporters for the fuels glucose, lactate and ketones will be measured in terms of their expression and function. The focus of ketone metabolism is a unique feature in this project as it not only addresses the effect on outcome, but also rigorously studies the appropriate biochemical pathways. Project 3 (Dr. Paul Vespa) addresses the topic of glucose substrate supply for human TBI patients primarily from the perspective of management of serum glucose concentration. Using different levels of insulin therapy, the effect on global and regional cerebral metabolism will be compared to neurochemical and anatomical markers of cell distress. In a creative cross over experimental design preliminary data will be collected for a future clinical trail. Project 4 (Dr. Neil Martin) will utilize the Kety-Schmidt technique to address how glucose is consumed differently in the human injured brain. The investigators within this program will determine the change in the consumption of cerebral glucose, the effects of changes in transporters, and the effects of enhancing or restricting glucose delivery and the potential use of alternative fuels. This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support.

Public Health Relevance

The critical care of traumatic brain injured patients in the intensive care unit currently relies on potentially inaccurate information regarding the role of glucose in cerebral metabolism. Patient care may be currently directed under the wrong assumptions, creating a false sense of security regarding the attempt to protect the brain from secondary insults. Our proposed studies are essential to understand the conditions that would enable appropriate metabolic therapy to be applied during the acute period after injury as well as remove potentially harmful interventions or treatment practices.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS058489-05
Application #
8460073
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Hicks, Ramona R
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,192,495
Indirect Cost
$404,329
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Wolahan, Stephanie M; Prins, Mayumi L; McArthur, David L et al. (2016) Influence of Glycemic Control on Endogenous Circulating Ketone Concentrations in Adults Following Traumatic Brain Injury. Neurocrit Care :
Prins, Mayumi L; Matsumoto, Joyce (2016) Metabolic Response of Pediatric Traumatic Brain Injury. J Child Neurol 31:28-34
Moro, Nobuhiro; Ghavim, Sima S; Harris, Neil G et al. (2016) Pyruvate treatment attenuates cerebral metabolic depression and neuronal loss after experimental traumatic brain injury. Brain Res 1642:270-7
Wong, Koon-Pong; Bergsneider, Marvin; Glenn, Thomas C et al. (2016) A semi-automated workflow solution for multimodal neuroimaging: application to patients with traumatic brain injury. Brain Inform 3:1-15
Shijo, Katsunori; Sutton, Richard L; Ghavim, Sima S et al. (2016) Metabolic fate of glucose in rats with traumatic brain injury and pyruvate or glucose treatments: A NMR spectroscopy study. Neurochem Int 102:66-78
Vespa, Paul; Tubi, Meral; Claassen, Jan et al. (2016) Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Ann Neurol 79:579-90
Goh, S Y Matthew; Irimia, Andrei; Torgerson, Carinna M et al. (2015) Longitudinal quantification and visualization of intracerebral haemorrhage using multimodal magnetic resonance and diffusion tensor imaging. Brain Inj 29:438-45
Glenn, Thomas C; Martin, Neil A; Horning, Michael A et al. (2015) Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects. J Neurotrauma 32:820-32
Chmayssani, Mohamad; Stein, Nathan R; McArthur, David L et al. (2015) Therapeutic intravascular normothermia reduces the burden of metabolic crisis. Neurocrit Care 22:265-72
Glenn, Thomas C; Martin, Neil A; McArthur, David L et al. (2015) Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis. J Neurotrauma 32:811-9

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