Project Summary
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-1a (HIF-1a) 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-1a 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-1a, 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-1a 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-1a [and its effect on p38 MAPK signaling] will be identified in the neonatal RADi mouse
with neuron-specific HIF-1a disruption or forced expression just induced before RADi. Furthermore, [inter-
regulation of HIF-1a 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-1a[/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.