# Mechanisms of Oligodendrocyte and Axonal Abnormalities After Perinatal Brain Injury

> **NIH NIH R37** · CHILDREN'S RESEARCH INSTITUTE · 2021 · $446,250

## Abstract

A major cause of chronic disability in survivors of premature birth is diffuse white matter injury (DWMI) and
hypomyelination. Altered development of the WM is directly associated with adverse outcomes, including
cerebral palsy, cognitive delay and neurobehavioral problems. The cellular pathophysiology underlying DWMI
and abnormal myelination is complex and not fully understood. WM glia, and particularly oligodendrocytes
(OLs) and their progenitors (OPCs), are susceptible to injury that often occurs in premature birth. We have
previously used an animal model of hypoxia (HX)-induced global WMI to demonstrate that OPCs display
delayed maturation, which results in abnormal myelination and altered WM function. We have uncovered major
aspects of the cellular dysmaturation pathology underlying HX-induced delayed myelination in corpus
callosum, including enhanced OPC proliferation associated with decreased OL differentiation, and disrupted
myelin ultrastructure. Our recent analysis of OL development in corpus callosum (CC) demonstrates that: i) the
prolonged proliferative state of OPCs and delayed OL differentiation in HX is a result of changes in HIF1α-
dependent expression and activity of the histone deacetylases Sirt1 and Sirt2, respectively; ii) HX reduces
synaptic glutamate (Glu) release from cortical pyramidal neurons on OPCs, which normally downregulates
OPC proliferation, and iii) HX compromises axonal integrity and function in SCWM, resulting in altered
axon/myelin interactions. Based on these results, we now propose to test the hypothesis that HX-induced
protracted WM immaturity arises from intrinsic (Sirt1 and Sirt2) and extrinsic (synaptic) dysregulation of OPC
proliferation and OL maturation, thus affecting axonal integrity and function. Firstly, we will establish the role of
Sirt2 as a crucial mediator of HX-induced delayed OL maturation in CC. Secondly, we will define the role of
non-cell autonomous, glutamate-mediated synaptic changes in regulating OPC proliferation and delayed OL
maturation in CC after HX. Finally, we will define the effects of HX and the role of delayed OL maturation on
axonal integrity/function in CC. Together, these studies will not only shed light on crucial cellular mechanisms
of HX-induced delay in WM maturation, but might also lead to the development of new therapeutic approaches
aimed at lessening the long-term neurological sequelae of premature birth.

## Key facts

- **NIH application ID:** 10242736
- **Project number:** 5R37NS109478-04
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Vittorio Gallo
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $446,250
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242736

## Citation

> US National Institutes of Health, RePORTER application 10242736, Mechanisms of Oligodendrocyte and Axonal Abnormalities After Perinatal Brain Injury (5R37NS109478-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242736. Licensed CC0.

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