Advanced medical interventions have resulted in greatly increased survival of severe preterm infants. Unfortunately, diffuse white matter injury (DWMI) is a frequent complication in these children resulting in chronic neurological disability. There are no effective therapies for the prevention or treatment of DWMI. Selective damage to oligodendrocyte progenitor cells (OPCs) and the resultant impaired myelinogenesis are central to DWMI. Strategies that would increase the survival and function of oligodendrocyte lineage cells would likely be of clinical benefit. DWMI is initiated by hypoxia, ischemia, and infection tht lead to oxidative stress, glutamate toxicity, and inflammation, which appear to be selectively toxic to OPCs. The integrated stress response (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 a subunit of eukaryotic translation initiation factor2 (eIF2a), resulting in inhibition of global protein synthesis and the selective expression of cytoprotective genes. The focus of this application is to investigate the ISR's ability to protect OPCs from stresses associated with premature birth using in vitro and in vivo model systems. Our hypothesis is that the enhancement of ISR activity in oligodendroglial lineage cells could provide therapeutic benefit to severe preterm infants, resulting in the amelioration of DWMI. In the proposed studies we will determine whether DWMI-associated cytotoxic insults activate the ISR in oligodendroglial lineage cells and whether the manipulation of the ISR modifies the response of these cells to the cytotoxic insults.
In aim 1 we will examine the response of OPCs in vitro to either oxygen-glucose deprivation (OGD) that models hypoxia- ischemia or in vitro intermittent hypoxia, both of which are associated with DWMI induction. These studies will include OPCs isolated from mouse mutants with genetic perturbations that either diminish or enhance the cell's ISR response. Survival and maturation of the OPCs will be quantitated.
In aim 2 we will use two mouse models of DWMI: an intermittent hypoxia model and an inflammation model, both of which result in delayed CNS myelination of the CNS. The role that the ISR plays in the oligodendroglial cells response in these models will be examined using the ISR mutants: OPC and oligodendrocyte numbers will be examined, as well as myelination and behavioral parameters.
In aim 3 we will determine if the drug guanabenz, which has been show to enhance/prolong the ISR response, will provide protection to OPCs in the in vitro and in vivo models described in the first two aims. These proof of principle drug studies will test the hypothesis that the pharmacological enhancement of the ISR will have therapeutic benefit for DWMI. In total, these studies will provide us with considerable insight into the role that the ISR plays in the response of oligodendroglial cells to the cytotoxic insults that are believed to be critical to the induction of DWMI. Importantly, the work has the potential to provide the foundation for a novel therapeutic approach for this devastating neurological disorder.
The proposed studies are relevant to public health because they directly address the childhood disorder diffuse white matter injury (DWMI), which arises as a consequence of very premature birth. The studies outlined will provide us with an increased understanding of the role that the cellular protective signaling pathway known as the integrated stress response (ISR) plays in the response of oligodendroglial cells to the cytotoxic insults that are believed to be critical to the induction of DWMI. Importantly, the work has the potential to provide the foundation for a novel therapeutic approach for this devastating neurological disorder.
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