This K08 proposal describes a 5-year training program for the development of an academic career in pediatric traumatic brain injury research. The overall objective for the Principal Investigator (PI), Susanna Scafidi, M.D., is to fully develop the scientific skill-set necessary to become an independent investigator focusing on new metabolic approaches to treating traumatic brain injury in children. The training program is designed to enable the PI to apply biochemical, cellular and molecular investigations to delineate mechanisms of metabolic dysfunction associated with pediatric traumatic brain injury. Gary Fiskum, Ph.D. the primary mentor;is an expert in mitochondrial bioenergetics, oxidative stress, and apoptosis following acute brain injury and has trained numerous junior faculty, postdoctoral fellows and graduate students. Alan Faden is a clinician-scientist with vast track record of studying brain trauma;Mary McKenna, Ph.D. is an internationally recognized expert in brain energy metabolism and brain development, and has a strong history of successful mentorship. In addition, advisory oversight committee of distinguished researchers will provide career guidance and scientific support. The University of Maryland School of Medicine offers a superb environment for basic science research as well as multidisciplinary collaborations. The training program consists of combination of specific didactic coursework, practical experimental techniques, experimental design and data interpretation. The research plan of this proposal is designed to elucidate specific alterations in aerobic brain energy metabolism after brain injury in developing brain and evaluate possible neuroprotective strategies. Traumatic brain injury (TBI) is the leading cause of pediatric morbidity and mortality, yet, there is no specific treatment and a significant number of head-injured children suffer from life-long disabilities. TBI is characterized by inhibition of cerebral aerobic energy metabolism, but the underlying mechanisms for cerebral energy failure are not well understood. Our findings suggest that energy failure post TBI is due to specific mitochondrial enzymes impairment, which precludes pyruvate, generated via glycolysis, from being utilized in the mitochondria for energy production. In addition to glucose, the developing brain can utilize alternative substrates, i.e. 2-hydroxybutyrate (BHB) and acetyl-L-carnitine (ALCAR), that bypass the inhibition of pyruvate metabolism. We hypothesize that (1) inhibition of cerebral aerobic energy metabolism after TBI is due to dysfunction of pyruvate dehydrogenase, astrocytic pyruvate carboxylase and (2) that exposure to pharmacologic levels of BHB and ALCAR will maintain cerebral oxidative energy metabolism and inhibit cell death. These hypotheses will be tested using a controlled cortical impact model of traumatic brain injury in immature 21-22 day old rats. Methods of approach to the Specific Aims needed to test these hypotheses include the use of animal models, behavioral tests, quantitative histopathology, immunohistochemistry, enzyme activity measurements, ex vivo NMR spectroscopy, state of the art in vivo Magnetic resonance imaging (MRI) and Magnetic resonance spectroscopy (MRS) and other methods in collaboration with the mentors will provide the PI with a broad experience in laboratory techniques that will greatly promote the candidate's career as a clinician/investigator in the field of pediatric critical care.
TBI is a leading cause of death and long-term disability in children in United States. The proposed studies aim to determine the cell specific metabolic changes occur after brain trauma in developing brain. The studies will also assess whether the natural capability of developing brain to use alternative substrates for energy may provide neuroprotection if these substrates are administered in pharmacologic doses shortly after TBI.
|Scafidi, Joseph; Hammond, Timothy R; Scafidi, Susanna et al. (2014) Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 506:230-4|