# White Matter Restoration in Vascular Cognitive Impairment and dementia

> **NIH NIH RF1** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $2,229,700

## Abstract

Abstract
Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia after Alzheimer’s disease.
Although the causes for VCID are not clear, increasing evidence suggests cerebral hypoperfusion is the dominant pathogenic
process. Cerebral hypoperfusion causes the death of oligodendrocytes, the only myelin (the key component in nerve fiber)
producing cells in CNS, leading to white matter injury (WMI) which is closely related to VCID. Thus, interventions targeted
at WMI—an area that remains poorly understood—may provide a new therapy for both WMI and VCID. We have
successfully reprogrammed reactive astrocytes into oligodendrocyte progenitor cells (iOPCs) by three transcription factors
(named SOA) in ischemic brain. Reprogrammed OPCs can proliferate/differentiate into mature oligodendrocytes, repair
WMI and improve sensorimotor and cognitive function. Thus, we intend to test the therapeutic potential of reprogrammed
oligodendrocytes in WM restoration and in cognitive dysfunction/memory loss in mouse models that mimic common carotid
artery (CCA) hypoperfusion caused by arteriosclerotic CCA stenosis. The central hypothesis is that in situ
reprogramming of activated astrocytes into oligodendrocytes can restore white matter integrity and improve long-
term cognitive recovery in VCID models induced by CCA hypoperfusion. The following three Aims are proposed:
Aim 1 will characterize the maturity of reprogrammed OPCs and their role in WM restoration in CCA hypoperfusion models
in both genders and the underlaying mechanism whether reprogrammed OPCs enhance WM restoration by enhancing axonal
remyelination and stimulating axonal sprouting. Aim 2 will test if iOPCs enhance long-term sensorimotor and cognitive
function as well as axonal function in the needle CCA hypoperfusion model in young and aged mice. Aim 3 will test if ICV
administration of recombinant SOA pool protein can reprogram reactive astrocytes into oligodendrocytes, restore WM
integrity, and improve cognitive recovery in a needle CCA hypoperfusion model. The proposed study is the first to
reprogram astrocytes in situ into viable oligodendrocytes and will provide a novel therapeutic approach for WMI and VCID
as well other CNS diseases that involve WMI.

## Key facts

- **NIH application ID:** 10030630
- **Project number:** 1RF1NS117509-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** GUODONG CAO
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,229,700
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030630

## Citation

> US National Institutes of Health, RePORTER application 10030630, White Matter Restoration in Vascular Cognitive Impairment and dementia (1RF1NS117509-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10030630. Licensed CC0.

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