# Mechanism of hypoxia mediated failure of oligodendrocyte generation

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $50,041

## Abstract

PROJECT SUMMARY
Nearly 1 out of every 10 children are born prematurely in the United States and although advancements in
perinatal care have resulted in the increased survival of preterm infants, many of these children go on to exhibit
neurodevelopmental deficits leading to significant cognitive and motor dysfunction. One of the most common
neurologic insults following preterm birth is diffuse white matter injury (DWMI), which is thought to arise from
hypoxic injury to the developing brain caused by the immature state of lung development and cerebral
vasculature and has no cure. White matter is required for communication within the central nervous system and
is primarily composed of myelin, which is a fatty sheath that surrounds neuronal axons to allow efficient action
potential propagation. Myelin is generated by mature oligodendrocytes, which arise via differentiation of
oligodendrocyte progenitor cells (OPCs). In the context of DWMI, hypoxia leads to apoptosis of cells of the
oligodendrocyte lineage followed by proliferation and failure of subsequent oligodendrocyte regeneration from
residual OPCs. This deficit in oligodendrocyte generation from OPCs following hypoxia can be abrogated by
knocking out hypoxia inducible factors (HIFs), which are DNA-binding transcription factors that accumulate under
hypoxia and are rapidly degraded in normoxia, in OPCs. However, the mechanism of how HIFs block
oligodendrocyte generation remains elusive. Leveraging our lab’s ability to generate large and pure populations
of OPCs, I performed ChIP-seq for HIF1a and H3K27Ac, a marker of active chromatin, in order to determine
putative HIF targets across the OPC genome. The top candidate target based on HIF1a binding as well as
enrichment of H3K27Ac suggested a transcription factor that has been shown to be important for stem cell
maintenance in tissues outside the central nervous system as a target of HIF in OPCs. I demonstrate that
overexpression of this transcription factor is sufficient to inhibit differentiation of OPCs to oligodendrocytes and
is upregulated following hypoxic injury in a mouse model of DWMI. This proposal seeks to further investigate
these findings by 1) utilizing a combination of cellular, molecular and genetic techniques to determine the
mechanism by which this transcription factor inhibits OPC differentiation 2) determining whether downregulation
of this transcription factor will facilitate recovery of oligodendrocyte formation following hypoxic injury in vitro and
3) characterizing the spatiotemporal dynamics of the upregulation of this transcription factor in vivo using a
mouse model of DWMI. The experiments outlined in this proposal will increase our understanding of mechanisms
that impede oligodendrocyte generation from OPCs under hypoxic conditions, and will uncover novel avenues
for therapeutic intervention for this highly prevalent and debilitating neurodevelopmental condition.

## Key facts

- **NIH application ID:** 9944313
- **Project number:** 5F30HD096784-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kevin Cameron Allan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,041
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944313

## Citation

> US National Institutes of Health, RePORTER application 9944313, Mechanism of hypoxia mediated failure of oligodendrocyte generation (5F30HD096784-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944313. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*