# Contribution of the X Chromosome to Sex Differences in Stroke

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $545,993

## Abstract

PROJECT SUMMARY
The overall goal of this proposal is to determine the sex chromosome genes that regulate ischemic stroke
sensitivity in the aged brain, and to explore the mechanisms underlying their regulatory role. It has been
increasingly recognized that stroke is a sexually dimorphic disease, however, the mechanisms underlying
these sex differences are not known. The elderly constitute the majority of stroke victims, and aged
women have a higher incidence, higher morbidity and higher mortality compared to age-matched men,
and these differences cannot be explained solely by exposure to gonadal hormones. Previous work has
shown the sex chromosome complement contributes to stroke sensitivity selectively in aged animals,
when gonadal hormones are equivalent between the sexes. We have found that there is an effect of the
X chromosome dosage (one X or XX) on microglial activation and immune responses. A prominent
feature of the aged X chromosome is that genetic silencing of genes on the second X chromosome
becomes incomplete, allowing for genes to escape from X-chromosome inactivation (XCI). This results
in higher expression of these X escapee genes in XX vs. XY cells in many tissues. Kdm6a and Kdm5c
are two X escapees that can regulate expression of interferon regulatory factors (IRFs) that are
responsible for microglial activation through epigenetic modification. Recent work has found Kdm6a and
Kdm5c are more highly expressed in microglia derived from aged female vs. male ischemic brain. Our
CENTRAL HYPOTHESIS is that X chromosome complement contributes to stroke sensitivity in the aged
brain, AND that the X escapee genes Kdm6a and Kdm5c epigenetically modify IRF1/3/4/5/8 in aged
microglia leading to sex-specific inflammatory responses. In Aim 1 we will use the XY* mouse model to
determine if the X chromosome contributes to stroke sensitivity in aged animals. Aim 2 will use an
inducible conditional knock out (ICKO) animal model to test the hypothesis that Kdm6a and Kdm5c sex
specifically impact on stroke outcomes through a mechanism of epigenetic modification, i.e.
demethylation of H3K27me3 and H3K4me3 marks respectively. Aim 3 will test the hypothesis that X
chromosome and Kdm6a/Kdm5c regulate microglial activation and immune responses through mediation
of IRF1/3/4/5/8 expression. These proposed studies will investigate the Kdm6a/5c-
H3k27me3/H3K4me3-IRFs signaling axes, a very innovative and novel area. We hypothesize that this
pathway plays a critical role in inducing sex differences in stroke in the aged.

## Key facts

- **NIH application ID:** 9923008
- **Project number:** 5R01NS108779-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Fudong Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $545,993
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923008

## Citation

> US National Institutes of Health, RePORTER application 9923008, Contribution of the X Chromosome to Sex Differences in Stroke (5R01NS108779-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9923008. Licensed CC0.

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