We propose to use our immature large animal models of traumatic brain injury (TBI) to accelerate basic science therapeutic discoveries to clinical trials for TBI in children. Because mitochondria play a key role in many primary and secondary pathologic pathways in TBI, we will use cyclosporin A (CsA) to rescue mitochondrial function, reduce cell death and improve neurofunction. Due to its safety profile in humans, pleiotropic effects, and success in multiple preclinical adult rodent TBI models, CsA (CsA) has exciting potential as a therapy for pediatric TBI. Because CsA is also off-patent and already in use in children for other indications, the results of the proposed preclinical therapy development plan can be translated rapidly to clinical trial. We determine the optimal dose of CsA for the spectrum of moderate TBI in the child, using our established immature porcine TBI models: focal lesions from controlled cortical impact and diffuse brain injury from rapid nonimpact head rotation. In addition, we include optimization at 1 hr after TBI to determine dosing strategies in the field, and at 6 hrs after TBI for hospital-based strategies. To enhance translation, we include clinically relevant physiological monitoring and current critical care management strategies. Furthermore, we use both histological and neurofunctional endpoints to identify agents that reduce brain injury acutely, and have sustained cognitive benefits.
In Aim 1, we will evaluate short-term dose response using short term terminal outcomes. For each start time and injury type, the most effective and the lowest dose with significant effect will continue to Aim 2.
In Aim 2 we test these dosing strategies for efficacy in neurocognitive outcomes, measured 6 days after injury, to identify the optimal dosing strategy to evaluate in pediatric TBI clinical trials.
In Aim 3 we will identify sex-specific cognitive recovery and toxicology responses to the optimal dose of CsA.
In Aim 4 we design the clinical trial from the porcine data and published human studies, and submit an IND application to the FDA. This state-of-the-art, innovative preclinical study design can be applied to future evaluations of other therapies longer treatment windows, other ages, other brain injuries, and to other agents that promote neurorecovery or repair.

Public Health Relevance

Traumatic brain injury (TBI) is the leading cause of death and acquired disability in childhood in the US. Despite the alarmingly high incidence, there are no specific treatments for TBI in children. We will use our immature large animal models of TBI with fidelity to children to create a new translational bridge between basic science discoveries in the rodent to pediatric clinical trials for TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Bellgowan, Patrick S F
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University of Pennsylvania
Biomedical Engineering
Schools of Engineering
United States
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Atlan, Lorre S; Smith, Colin; Margulies, Susan S (2018) Improved prediction of direction-dependent, acute axonal injury in piglets. J Neurosci Res 96:536-544
Atlan, Lorre S; Lan, Ingrid S; Smith, Colin et al. (2018) Changes in event-related potential functional networks predict traumatic brain injury in piglets. Clin Biomech (Bristol, Avon) :
Pasquesi, Stephanie A; Margulies, Susan S (2017) Failure and Fatigue Properties of Immature Human and Porcine Parasagittal Bridging Veins. Ann Biomed Eng 45:1877-1889
Coats, Brittany; Binenbaum, Gil; Smith, Colin et al. (2017) Cyclic Head Rotations Produce Modest Brain Injury in Infant Piglets. J Neurotrauma 34:235-247
Pasquesi, Stephanie A; Liu, Yishan; Margulies, Susan S (2016) Repeated Loading Behavior of Pediatric Porcine Common Carotid Arteries. J Biomech Eng 138:
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Ferguson, Michael A; Sutton, Robert M; Karlsson, Michael et al. (2016) Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction. J Bioenerg Biomembr 48:269-79
Maltese, Matthew R; Margulies, Susan S (2016) Biofidelic white matter heterogeneity decreases computational model predictions of white matter strains during rapid head rotations. Comput Methods Biomech Biomed Engin 19:1618-29
Margulies, Susan; Anderson, Gail; Atif, Fahim et al. (2016) Combination Therapies for Traumatic Brain Injury: Retrospective Considerations. J Neurotrauma 33:101-12
Olson, Emily; Badder, Carlie; Sullivan, Sarah et al. (2016) Alterations in Daytime and Nighttime Activity in Piglets after Focal and Diffuse Brain Injury. J Neurotrauma 33:734-40

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