# Non-coding RNA regulation of sex differences in stroke

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $361,180

## Abstract

Stroke remains the second leading cause of death worldwide and the primary cause of long-term disability in the
US. Although pre-clinical studies have identified hundreds of potential drug agents, the only pharmacological
treatment available remains early reperfusion with thrombolytics. A major factor for translational failure may be
the overwhelming use of young male rodents in pre-clinical research, and lack of sex-specific design and analysis
in clinical trials. Stroke is a sexually dimorphic disease with sex differences in incidence, prevalence, and
outcome. Mitochondria mediate post-ischemia cell death in both males and females, but in different manners.
Non-coding RNAs, including microRNAs (miRs), are upstream regulators of genes that regulate cell survival and
mitochondrial function. In young adult male animals, miRs have been established as central regulators in the
cellular response to stroke, however their role in females or aged animal cohorts represents a critical knowledge
gap. Our prior studies (2, 4) and preliminary evidence suggest age-related differences between females and
males in expression of select miRs and their targets following stroke. The overarching hypothesis of these Aims
is that expression and function of miR-181a and miR-200c is a critical determinant of sexual dimorphism in stroke
outcomes. To test this, we will first compare aged (20 month old) female and male mice using the middle cerebral
artery occlusion (MCAO) model of experimental stroke, then compare primary female and male neuronal and
astrocyte cultures utilizing in vitro ischemia. Preliminary evidence in aged animals reveals only a modest post-
MCAO miR-181a response that is limited to females, while comparatively, a pronounced miR-200c response
occurs in both sexes. Moreover, our preliminary evidence implies sex-differences in miR-181a and miR-200c
gene targeting. In Aim 1, we will first compare protection with post-MCAO IV treatment of anti-miR-181a or anti-
miR-200c in aged males and females. Then, we will assess the long-term cell-specific and sex-specific response
in miR-181a and miR-200c to MCAO. Next, we will compare sustained post-MCAO miR-200c inhibition on long-
term neuro-recovery between aged males and females, with the basis that preliminary evidence implies female-
specific targeting of the neurotrophic protein reelin by miR-200c. In Aim 2, we will: 1) focus on the roles of miR-
181a and miR-200c in differences in regional (core versus penumbra) post-stroke disruption in mitochondrial
function between aged males and females; and, 2) determine the roles of miR-181a and miR-200c in cell-type,
and sex-specific alterations in oxidative phosphorylation and disruptions in cytosolic and mitochondrial Ca2+-
handling following in vitro ischemia. In Aim 3 we will first define cell-type and sex-dependent differential gene
targeting by miR-181a (Grp78 and XIAP) and miR-200c (XIAP, sirtuin-1, reelin). Finally we will determine whether
observed differenti...

## Key facts

- **NIH application ID:** 10401426
- **Project number:** 5R01NS107445-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Creed Michael Stary
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,180
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401426

## Citation

> US National Institutes of Health, RePORTER application 10401426, Non-coding RNA regulation of sex differences in stroke (5R01NS107445-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401426. Licensed CC0.

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