# Sex Differences in Cardiometabolic Health and Disease

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $1,467,135

## Abstract

Overall
SUMMARY
 The objective of our SCORE on “Sex Differences in Cardiometabolic Health and Disease” is to identify
factors that determine sex-specific cardiometabolic disease risk, which may lead to better diagnosis and
treatment for both sexes. A unique feature of our program is the investigation of sex differences from multiple
perspectives, including effects of estrogen, of XX vs. XY sex chromosome genes, and of genetic variation
among individuals. Our program consists of three research projects and three cores, and will use preclinical
mouse models, human induced pluripotent stem cell lines (iPSCs), and existing human population datasets
(genomic, transcriptomic, proteomic, and metabolomic) to translate findings from our model systems to
humans. Project 1, “Epigenetic sex determinants of cardiometabolic disease and prevention,” will build on our
identification of X and Y chromosome genes that influence sex differences in both the development of diet-
induced obesity and susceptibility to adverse effects of statin drugs. We will elucidate the role of three X-Y
histone demethylase genes in epigenetic sex differences in mouse adiposity and human adipocyte
differentiation. We will also identify the epigenetic determinants of sex-biased statin adverse effects on
mitochondrial function. Project 2, “Gene-by-sex interactions in heart failure with preserved ejection fraction
(HFpEF),” seeks to understand the mechanisms underlying increased prevalence of HFpEF in women
compared to men. Using a “systems genetics” approach and a panel of genetically distinct mouse strains, the
goals are to understand sex differences in HFpEF traits at the molecular level, including the role of gonadal
hormones and sex chromosomes, and to create sex-specific biologic networks that can be generalized to
humans. Recent findings implicate sex differences in the mitochondrial enzyme, ACSL6, as causal for HFpEF,
and further studies will characterize the role of mitochondrial dysfunction in HFpEF. Project 3, “The impact of
estrogen receptor alpha on cardiomyocellular metabolism and health,” will test the hypothesis that estrogen
receptor alpha action in cardiomyocytes impacts mitochondrial metabolism, cardiac tissue integrity and heart
function. Findings with unique cardiomyocyte estrogen receptor alpha knockout or overexpression mouse
models will then be integrated with human data in collaboration with our Human Translational Bioinformatics
Core. The Human Translational Bioinformatics Core will serve as hub for computational analyses to
translate findings from the three Projects for association and relevant to cardiometabolic traits in humans using
existing large human genetic and –omics datasets. The Career Enhancement Core will foster research in sex
differences in metabolism by administering a Pilot & Feasibility grant program, and will educate researchers
and students about SABV through courses, hands-on laboratory ‘bootcamp,’ and a library of SABV videos. The
Administr...

## Key facts

- **NIH application ID:** 10919840
- **Project number:** 5U54HL170326-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Karen Reue
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,467,135
- **Award type:** 5
- **Project period:** 2018-09-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919840

## Citation

> US National Institutes of Health, RePORTER application 10919840, Sex Differences in Cardiometabolic Health and Disease (5U54HL170326-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10919840. Licensed CC0.

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