# sGC oxidative stress controls cerebral blood flow and cognitive function

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $429,000

## Abstract

Project Summary
 Current US demographic trend indicates that age-related dementia is becoming a serious public
health crisis. Its prevalence and severity is expected to increase substantially in the near future. Currently,
neurodegenerative diseases lack effective treatments. Therefore, understanding the processes that
contribute to these diseases is needed for the design of effective and preventive treatment measures.
Significant decrease in cerebral blood flow (CBF) is a major hemodynamic alteration leading to
neurodegeneration and age-related cognitive decline. Nitric Oxide (NO)-dependent vasomotor reactivity
of cerebral arterioles plays a central role in regulation of cerebrovascular hemodynamics and adequate
brain blood perfusion. The majority of beneficial effects of NO are mediated via its receptor, soluble
Guanylyl Cyclase (sGC). Age-dependent decline of NO/cGMP signaling underlies impaired ability of
patients with a wide range of neurodegenerative diseases to learn and process new information.
However, the molecular mechanisms contributing to sGC deactivation in these cases are poorly
understood. Oxidation or loss of sGC-bound heme contributes to the decline of NO-sGC function and
leads to sGC protein degradation. Our Preliminary data indicate that loss and oxidation of sGC heme is
one of the factors associated with aging. We therefore propose that oxidation-induced loss of sGC heme
negatively affects the regulation of CBF and exacerbate the decline of neurologic and cognitive functions
with aging. Therefore, augmenting sGC function by supporting heme metabolism or applying heme-
independent sGC activators should prevent/delay age-related decline in CBF and associated neurologic,
memory, and cognitive functions. If proven, our hypothesis will stimulate the development of new
therapeutics targeting cerebrovascular dysfunctions. There will be two Specific Aims: Aim 1 will
determine how changes in oxidative state of sGC-bound heme affect CBF and cognitive functions in
ageing mice. Aim 2 will establish the effect of heme- and sGC-targeting interventions on the age-
dependent decline of sGC function in brain. Our data will provide empirical evidence that the integrity
and redox state of sGC heme is essential for regulation of CBF and contributes to the decline of
neurological/cognitive function. We also aim to provide proof for the principle that pharmacological and
dietary countermeasures targeting heme-deficient sGC in cerebral vasculature will alleviate
neurodegeneration and improve cognitive decline.

## Key facts

- **NIH application ID:** 10373741
- **Project number:** 1R21AG071999-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Iraida G. Sharina
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2022-01-15 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373741

## Citation

> US National Institutes of Health, RePORTER application 10373741, sGC oxidative stress controls cerebral blood flow and cognitive function (1R21AG071999-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10373741. Licensed CC0.

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