# Cyb5R3 and Vascular-related Dementia

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

## Abstract

Abstract: Worldwide, stroke and dementia account for half of all neurological disorders.
Vascular cognitive
impairment and dementia (VCID) is the second common cause of dementia. The key feature of VCID is diffuse
white mater lesions (WML), detected as white matter hyperintensities (WMHs) on MRI scans. The neurological
pathology of WMHs includes blood brain barrier disruption, myelin loss, axonal disruption, and astrogliosis. It is
well established that hypertension and arteriosclerosis stenosis are the most significant risk factors for dementia
epidemics. Currently, there are no therapies for symptomatic treatment of VCID and the underlying molecular
and cellular mechanisms for cognitive deficits are not well understood. Associated with neurovascular decline
is diminished nitric oxide (NO) signaling in neurons, vascular cells and innate immune cells providing one
possible mechanism contributing to vascular dysfunction, WMH and dementia. We recently identified
cytochrome b5 reductase 3 (Cyb5R3) as a soluble guanylyl cyclase (sGC) heme iron reductase in vascular
smooth muscle, which reverses sGC oxidation (Fe3+→Fe2+) during oxidative stress to preserve NO signaling
needed for vascular relaxation. In the human population, over 40 genetic polymorphisms in Cyb5R3 have been
identified. Of particular interest is the missense variant at position 117 of the soluble protein or position 150 of
the membrane protein, wherein the amino acid threonine is substituted for a serine residue. This is a high
frequency genetic variant in individuals with African Ancestry (23% minor allele frequency) and found in less than
1% of any other race. Using a bilateral carotid artery stenosis model which mimics many features of vascular-
related dementia, we will test if 1) mice carrying the T117S variant show accelerated neurovascular decline in
response to VCID and 2) if sGC modulator therapies reverse the complications associated with VCID.

## Key facts

- **NIH application ID:** 10113978
- **Project number:** 3R01HL128304-05S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Adam Carl Straub
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 3
- **Project period:** 2016-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113978

## Citation

> US National Institutes of Health, RePORTER application 10113978, Cyb5R3 and Vascular-related Dementia (3R01HL128304-05S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10113978. Licensed CC0.

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