# Mechanisms for vascular regulation of remyelination in white matter injury

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $99,236

## Abstract

Project Summary
Cerebral microvascular disease (CMD) causes white matter injury and is a major contributor of the vascular
contributions to cognitive impairment and dementia (VCID), including as the most common co-morbidity to
clinical Alzheimer’s Disease. Chronic vascular risk factors such as obesity accelerate the progression of CMD
by primarily damaging brain endothelial cells. Risk factor-induced changes in cerebral endothelial cells contribute
to an increased risk of dementia. The molecular changes in cerebral endothelial cells caused by chronic
cerebrovascular risk factors remain unknown yet are critical to designing therapies to prevent and repair ischemic
white matter lesions thereby lessening the burden of VCID. We propose that a central mechanism of CMD
progression is dysregulated signaling in brain endothelial cells damaged by chronic vascular risk factors. Using
endothelial cell-specific transcriptional profiling, we show that chronic endothelial injury resulting from obesity
results in abnormal vascular expression of an interleukin/chemokine signaling pathway. This molecular pathway
results in dysregulated vascular-oligodendrocyte progenitor cell (OPC) signaling. OPCs are a critical progenitor
cell population in brain white matter that respond to injury and are responsible for remyelination. Preliminary data
demonstrate that chronically injured endothelial cells up-regulate IL-17 receptor b (IL-17Rb) and its effector
chemokine CXCL5. Though many inflammatory pathways may play a role in brain ischemia, we show that this
is the major inflammatory pathway that is active in endothelial cells injured by this chronic vascular risk factor.
Critically, we further demonstrate that endothelial expression of CXCL5 results in the chemotaxis of OPCs to the
vasculature, limiting their ability to remyelinate after a focal white matter ischemic lesion. Using gain and loss of
function studies at the in vitro, in vivo, and functional levels after stroke, we will dissect the molecular pathways
involved in dysregulated vascular-OPC signaling and identify a role for chemokine signaling in regulating white
matter injury underlying VCID. Studies in Aim 1 will use an in vitro conditioned medium paradigm to identify the
precise signaling mechanisms in endothelial cells that promote CXCL5 expression while identifying the
necessary receptors on OPCs that regulate migration and differentiation. In Aim 2, we will broadly determine the
role of chemokine receptor activation on the ability of OPCs to differentiate and remyelinate after stroke using
CXCR2 knockout and small molecule antagonism. Finally, we will show in Aim 3 that blocking the expression of
CXCL5 in white matter endothelia can reduce cognitive and motor impairment associated with focal white matter
stroke by promoting remyelination within the peri-infarct tissue adjacent to stroke. Together, these studies
establish new molecular mechanisms for the vascular regulation of remyelination as critical to t...

## Key facts

- **NIH application ID:** 11036202
- **Project number:** 3RF1NS114336-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jason D Hinman
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,236
- **Award type:** 3
- **Project period:** 2024-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11036202

## Citation

> US National Institutes of Health, RePORTER application 11036202, Mechanisms for vascular regulation of remyelination in white matter injury (3RF1NS114336-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11036202. Licensed CC0.

---

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