HIF-1/p38 MAPK pathway in rotational acceleration-deceleration neonatal brain injury

University Of Louisville, Louisville KY

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Abstract

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-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.