# Targeting Cerebrovascular Dysfunction for White Matter Protection

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $391,250

## Abstract

Project Summary:
A healthy cerebrovascular system is necessary for the brain to function optimally. Vascular dysfunction can
cause vascular cognitive impairment and dementia (VCI/D), a devastating disorder that leads to tremendous
economic and social burdens on society. These vascular changes lead to diffuse white matter (WM) injury,
which not only cause vascular dementia, but also accelerate other types of dementia, including Alzheimer’s
disease. However, our understanding of the mechanisms of vascular abnormality to WM injury on the
progression of VCI/D is limited. Using both in vitro and in vivo methods, we have obtained exciting preliminary
results suggesting that hypoperfusion-initiated endothelial damage, oxidative stress to neurons and
oligodendrocyte precursor cells, and protein overload in the cortex play critical roles to WM injury and cognitive
impairments. Activating Nrf2a master transcription factor that controls the expression of cytoprotective
enzymesprotects the brain against WM injury and cognitive impairments, whereas suppressing Nrf2
exacerbates WM injury and cognitive impairments. The purpose of this proposal is to further investigate the
mechanisms responsible for the cell-specific Nrf2 protection against WT injury and cognitive impairment. The
overall hypothesis is that Nrf2 attenuates oxidative stress following cerebral hypoperfusion, thereby decreasing
BBB leakage and increasing clearance of neurotoxic proteins, allowing preservation of WM and improved
cognitive outcomes. Three specific aims are proposed: Aim 1 tests the hypothesis that Nrf2 activation
preserves WM integrity and long-term cognitive functions in experimental VCI/D. Aim 2 tests the hypothesis
that VE-Cad is an Nrf2 target gene and that EC-specific Nrf2 contributes to the BBB and WM protections in
mice after 2VS. Aim 3 tests the hypothesis that CNPase is an Nrf2 target gene in OPC and that PC-specific
OPC Nrf2 contributes to OPC differentiation and WM repairs in mice after 2VS. The investigation of the
protective actions of Nrf2 may help to clarify the underlying mechanism of vascular contribution to WM injury
and dementia, and develop future therapies that boost endogenous cytoprotection in vascular dementia
victims.

## Key facts

- **NIH application ID:** 9919010
- **Project number:** 5R01NS103810-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Milos D Ikonomovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919010

## Citation

> US National Institutes of Health, RePORTER application 9919010, Targeting Cerebrovascular Dysfunction for White Matter Protection (5R01NS103810-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9919010. Licensed CC0.

---

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