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Abstract

In this thesis two distinct but related studies are presented. The first study is on the role of the integrated stress response (ISR) in a hypoxia induced white matter disorder of prematurity, and the second is on the effect of neonatal hypoxia on myelination of the peripheral nervous system (PNS). The goal of both studies is to furthering our understanding of hypoxia induced injuries suffered by premature infants with the hope of informing the future development of novel therapeutics. With advancement in medical interventions a greater percentage of premature infants, especially those weighing less than 1500g, are surviving. Unfortunately, neurological disabilities due to white matter injury continue to be a leading cause of morbidity among survivors of premature birth. While in past decades the predominant lesion in the premature brain was necrotic white matter injury caused by hypoxia and ischemia, today the most frequently observed lesion is diffuse white matter injury (DWMI) caused by hypoxia alone. Hypoxia leads to selective damage of oligodendrocyte progenitor cells (OPCs), therefore, a better understanding of the response of OPCs to hypoxia is crucial for developing strategies that would increase their survival and function. The ISR is a conserved stress-induced signaling pathway that is activated by, and provides protection to, a variety of cytotoxic insults. ISR signaling leads to the phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α), resulting in inhibition of global protein synthesis and the selective expression of cytoprotective genes. Importantly, hypoxia is an activator of the ISR through the eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), indicating a potential role for the ISR in hypoxia-induced DWMI. We hypothesized that the PERK arm of the ISR plays an active role in hypoxia induced DWMI and that inhibition of this pathway will exacerbate DWMI while enhancement of the PERK pathway will protect oligodendrocytes and myelin from hypoxia induced DWMI. We demonstrate that in vitro hypoxia activates the ISR in primary OPCs and that genetically inhibiting the PERK arm of the ISR in differentiating OPCs increases their susceptibility to in vitro hypoxia. We also show that an in vivo mild chronic hypoxia (MCH) model of DWMI activates part of the ISR. Nonetheless, genetic inhibition of the PERK pathway does not have a significant effect on MCH-induced DWMI, and moreover, genetic enhancement of the ISR exacerbates the negative effects of MCH. In addition, we establish a new severe acute hypoxia (SAH) model of DWMI that also activates part of the ISR, although neither genetic inhibition nor genetic enhancement of the ISR appear to have a significant effect on SAH-induced DWMI. These studies suggest that while the ISR protects OPCs from severe hypoxia in vitro, it does not play a major role in either mild chronic or SAH-induced DWMI and is therefore not likely to be a valid target for therapies aimed at improving neurological outcome in preterm neonates with hypoxia-induced DWMI. The adverse effects of neonatal hypoxia, associated with premature birth, on central nervous system (CNS) myelination are well known. However, the effects of neonatal hypoxia on PNS myelination have not been addressed. Damage to Schwann cells in the PNS can lead to myelin disorders that cause significant motor deficits. Furthermore, evidence suggests that motor impairments are a risk factor for behavioral and cognitive deficits experienced by approximately 50% of survivors of premature birth. A better understanding of the effects of neonatal hypoxia on PNS myelination could provide novel opportunities for therapeutic intervention. We hypothesized that neonatal hypoxia would lead to hypomyelination of the PNS with sustained motor deficits. We demonstrate that neonatal hypoxia results in thinner PNS myelin and delayed development of axon bundles in mice leading to electrophysiological and motor deficits that persist into adulthood. These findings provide support for a role of hypoxic damage to the PNS in persistent motor deficits commonly experienced by premature infants and suggest that therapies designed to protect PNS myelin may improve clinical outcomes in premature infants.

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