Shaken baby syndrome (SBS) or shaken impact syndrome is a form of abusive head injury (AHT) in which a child is subjected to severe repetitive rotational acceleration-deceleration (RAD) forces without blunt impact to the head. Approximately 25 percent of SBS victims die as a result of their injuries. Survivors may suffer permanent physical, neurological and mental disabilities. Little is known about the etiology, pathophysiological implications, and underlying mechanisms, and preventive/therapeutic interventions are lacking. The preliminary findings in a neonatal mouse model of RAD injury (RADi) show that RADi in the developing brain results in [global cerebral blood hypoperfusion], cerebral accumulation of hypoxia-inducible factor-1? (HIF-1?) and activation of its downstream target molecules such as [glucose transporter 1 (Glut 1), nuclear factor like 2 (Nrf2)], heme oxygenase-1 (HO-1), and aquaporin 4 (AQP4). [At the later stage, HIF-1? is significantly down-regulated with activation of p38 mitogen-activated protein kinase (MAPK), followed by neuronal degeneration and behavioral deficits. Surprisingly, daily acute intermittent hypoxia (dAIH) post- conditioning intervention promotes accumulation of HIF-1?, inhibition of p38 phosphorylation, and recovery of cognitive function in RADi mice.] To date, knowledge of the HIF-1 signaling pathway in the central nervous system (CNS) is still limited and controversial. The precise role of HIF-1? signaling has never been explored in SBS and relevant animal models. In this proposal, it is hypothesized that neuronal activation of HIF-1 signaling plays a [neuroprotective role via inhibiting p38 MAPK activation] following RADi in developing brains. The precise function of HIF-1? [and its effect on p38 MAPK signaling] will be identified in the neonatal RADi mouse with neuron-specific HIF-1? disruption or forced expression just induced before RADi. Furthermore, [inter- regulation of HIF-1? and p38 MAPK as well as their therapeutic potentials will be investigated in sham and RADi mice administrated with vehicle solution, prolyl-4-hydroxylase (PHD) inhibitor, and p38 MAPK inhibitor, respectively.] Effects of HIF-1?[/p38 MAPK pathways] on RADi brain will be assessed by quantifying cardiorespiratory function, brain water content, gene expression, neuronal degeneration and apoptosis, [cerebral blood perfusion, magnetic resonance spectroscopy,] and behavior. These findings will likely elucidate the underlying pathological mechanism(s) of RADi and functional deficits in SBS, and suggest early-stage interventions to treat SBS-related neurological and/or psychological sequelae.
Little is known about the etiology, pathophysiological implications, and the underlying mechanisms of shaken baby syndrome (SBS). The precise laboratory diagnosis and preventive/therapeutic interventions are lacking. The proposed project will identify the [neuroprotective role] of HIF-1? signaling in the developing brain using a novel neonatal mouse model of repetitive rotational acceleration-deceleration brain injury, which may reveal the pathological mechanism(s) of SBS and potential therapeutic target(s) to prevent functional neurologic decline, facilitate de novo regeneration, and restore function (especially for cognition) following brain injury.
