A major cause of chronic disability in survivors of premature birth is the development of periventricular leukolomalacia and ventriculomegaly, with subsequent cerebral palsy and cognitive impairment. The primary pathological hallmark of this condition is white matter (WM) atrophy resulting from the loss of myelin and oligodendrocytes. The cellular pathophysiology underlying the altered development of WM in premature children is complex and not fully understood. WM glia, particularly progenitors for oligodendrocytes and astrocytes, is susceptible to hypoxic injury. Oligodendrocytes and astrocytes play essential roles in WM integrity and function, therefore a thorough understanding of the cellular mechanisms that, lead to glial maldevelopment and damage after hypoxia (HX) is necessary. The identification of molecular mechanisms that are crucial to regulate glial regeneration will enable: i) manipulation of glia and progenitor cells to preserve WM integrity, and ii) enhanced regeneration and recovery from postnatal HX induced injury. We investigated the role of EGFR signaling in developmental myelination after HX in a CNP-hEGFR mouse, in which all oligodendrocyte precursor cells overexpress the hEGFR. Our preliminary analysis shows that enhanced EGFR activity protects oligodendrocytes from HX-induced damage and promotes a recovery response that involves activation of oligodendrocyte progenitor cells (OPCs). Based on these findings, we are planning to investigate the role of EGFR signaling in WM development after hypoxic damage. First, we will define and compare development of WM glia and myelination in WT and CNP-hEGFR mice after HX. A comparative cellular and molecular analysis of glial progenitors in the subventricular zone will also be performed. Second, we will determine the extent of functional myelination in WT and CNP-hEGFR mice after HX by electrophysiological analysis. Diffusion tensor imaging (DTI) and behavioral evaluation will also be used to determine the extent of structural and functional recovery. Finally, we will assess whether maintaining hypoxic mice in an enriched environment improves WM glia recovery and myelination, and whether enhanced EGFR signaling adds further to the beneficial effects of enriched environment. Together, these studies will not only shed light on crucial cellular and molecular mechanisms of WM injury and recovery, but might also lead to the development of new therapeutic approaches aimed at lessening the long-term neurological sequela of premature birth.

Public Health Relevance

The goal of Project 3 is to understand whether chronic sublethal hypoxia impairs the survival and the maturation of oligodendrocytes in the developing white matter, and whether this can be overcome by enhancing oligodendrogenesis from endogenous progenitor cells. Understanding the cellular signals that promote oligodendrocyte generation and survival after injury will allow developing new means of therapeutic intervention to the neurobehavioral sequelae of preterm birth.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Yale University
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