# Oligodendrocyte Progenitors and Mechanisms of Human Vascular White Matter Injury

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $768,848

## Abstract

Project Summary
Progress to define mechanisms of white matter injury (WMI) in vascular cognitive impairment and dementia
(VCID) has been hampered by fundamental gaps in our understanding of the vascular and glial mechanisms
related to the pathogenesis of remyelination failure, a hallmark of VCID. We propose a highly integrated
analysis of the interplay between microvascular and oligodendrocyte progenitor cell (OPC) contributions to
VCID pathogenesis. We will mechanistically link dysfunctional reactivity and inflammation of the WM
vasculature to novel perivascular disturbances in OPC responses to WMI that appear central to myelination
failure in VCID. We will test the over-riding hypothesis that dysfunction of white matter arterioles
establishes selectively vulnerable zones of perivascular WMI from oxidative and nitrosative stress that
result in functionally dysmature white matter niches associated with aberrant OPC migration,
proliferation and differentiation to myelinating oligodendrocytes. This hypothesis is supported by our
recent studies (Bagi et al., Ann Neurol 2018; 83:142-152) that identified selectively impaired vasodilator
function of human WM penetrating arterioles in microvascular brain injury (mVBI) in similar white matter
regions where disrupted maturation of pre-myelinating OPCs occurred. In all three aims, we will employ a
unique collection of human rapid autopsy brains from a large cohort of cases with VCID where white matter
hyperintensities (WMHs) were identified by ante-mortem MRI. Although WMHs are widely used clinically to
identify patients at risk for cognitive decline, their pathological basis is poorly defined. In aim 1, we will define
mechanistic relationships among impaired cholinergic vasodilation of white matter arterioles, high vascular wall
shear stress and WMI arising from augmented production of reactive oxygen and nitrogen species. We will test
the hypothesis that impaired cholinergic vasodilation exposes endothelial cells in WM penetrating arterioles to
a high level of wall shear stress, which induces augmented production of reactive oxygen and nitrogen species
in mVBI. In aim 2, we will define molecular disturbances in the OPC-vascular niche that contribute to
myelination failure in mVBI. We will focus on the role of vascular factors in aberrant OPC migration,
proliferation and maturation. We will capitalize on several new lines of data that demonstrate novel
perivascular injury responses of OPCs at the level of WM arterioles and capillaries. In aim 3, we will define
vascular extracellular matrix mechanisms related to hyaluronic acid (HA)-mediated dysfunction of WM
arterioles. We will integrate approaches using murine and human vessels to define the role of various forms of
HA in vascular inflammation, loss of vascular integrity and abnormal leukocyte adhesion and extravasation
across the vascular endothelium. Our over-riding objective is to provide a mechanistic molecular explanation
for the distinct OPC-vascul...

## Key facts

- **NIH application ID:** 9970554
- **Project number:** 5R01NS105984-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Stephen Arthur Back
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $768,848
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970554

## Citation

> US National Institutes of Health, RePORTER application 9970554, Oligodendrocyte Progenitors and Mechanisms of Human Vascular White Matter Injury (5R01NS105984-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970554. Licensed CC0.

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