# Mechanisms of oxysterol-induced oligodendrogenesis

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $508,508

## Abstract

Abstract:
White matter injury is the most common neonatal brain injury leading to poor neurologic outcomes in premature
infants. This injury results in both focal and/or diffuse losses of oligodendrocytes, the myelinating cells in the
brain. Hypoxia and inflammation are common and important risk factors within this vulnerable population and
there are no treatment options available. A significant challenge to the development of novel treatment strategies
for brain injury in neonates is the appropriate concern for safety. To de-risk innovative therapeutic development
in this field, we focused on the identification of endogenous signaling molecules present in human maternal
breast milk to further develop into safe and effective therapies for neonates. We identified multiple oxidized
cholesterols (oxysterols) in human maternal breast milk that promote oligodendrocyte fate specification in
postnatal neural stem cell populations via a sonic hedgehog-dependent mechanism. Following neonatal WMI,
systemic administration of breast milk-associated oxysterol reversed the loss of periventricular oligodendrocytes
and rescued associated motor deficits in our neonatal inflammatory WMI mouse model. Our long-term objective
is to develop safe and effective therapy that mitigates the neurologic deficits of neonatal WMI. The objective of
this proposal is to test the efficacy of 20HC therapy in a chronic hypoxia model and determine the molecular
mechanism(s) of induced oligodendrogenesis. Our central hypothesis is that oxysterol therapy will improve
myelination in hypoxia-induced neonatal WMI through stem cell-derived oligodendrogenesis and induced
oligodendrocyte precursor cell (OPC) maturation. The rationale is that determining the efficacy of oxysterol
therapy in animal models of hypoxia will lead to critical development of novel therapies to treat hypoxia-induced
neonatal brain injuries. In Amis 1 & 2 this proposal we will test the efficacy of 20HC therapy in a neonatal mouse
model of chronic hypoxia. Using separate genetic tools, we can determine the cellular behavior of both
endogenous neural stem cells (Aim 1) as well as OPCs (Aim 2) in response to therapy. In our final Aim 3, we
will explore the impact of oxysterol-induced posttranslational protein modifications on Sox10. Sox10 is a critical
transcription factor that regulates oligodendrocyte maturation. Because oxysterols are found in breast milk, this
approach may be further developed into a novel and safe therapeutic strategy to mitigate myelin injuries including
those in the neonatal period. A comprehensive understanding of the molecular mechanisms of oxysterol-induced
OPC maturation may support further testing in models of adult myelin disorders including, multiple sclerosis
(MS), traumatic brain injury, and stroke.

## Key facts

- **NIH application ID:** 10745688
- **Project number:** 5R01NS114578-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Eric J Benner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,508
- **Award type:** 5
- **Project period:** 2019-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745688

## Citation

> US National Institutes of Health, RePORTER application 10745688, Mechanisms of oxysterol-induced oligodendrogenesis (5R01NS114578-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10745688. Licensed CC0.

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