Uncovering the missing X factors to understand sex bias in cardiovascular disease: EscapeX

Programme(s): HORIZON.1.1 - European Research Council (ERC) 

Topic(s): ERC-2022-STG - ERC STARTING GRANTS

Call for proposal: ERC-2022-STG

Funding Scheme: HORIZON-ERC - HORIZON ERC Grants

Grant agreement ID: 101078764

Objective:

Cardiovascular diseases (CVD) occur and progress differently in men and women, and the risk dramatically increases with age. Hormone differences have been suggested to account for the sex difference by observing that younger women are regularly protected from CVD until post-menopause. However, hormone replacement therapies failed to provide cardioprotection, suggesting that other biological factors contribute to sex disparities in CVD development. Other likely contributors to sex bias are genes that escape female X chromosome inactivation, an understudied epigenetic phenomenon that has so far not been linked to sex differences in CVD. These so-called escaper genes have twice the gene dose in females compared to males and thus are likely to contribute to sex-based differences. EscapeX aims to identify sex-specific protective mechanisms by disentangling the impact of hormones and sex chromosomes on sex bias in CVD. First, we will combine the transgenic FCG mouse model, in which the sex chromosome complement (XX or XY) is independent of the gonadal hormones, with the pressure overload heart failure model, which shows a sex-specific phenotype. Next, EscapeX uses our established escaper detection pipeline to map and characterize escaping during cardiac aging and disease. The resulting dataset will uncover the escaper gene function, the extend of lineage-specific escaping, and how the escaper landscape changes during aging and disease. Building on those findings, EscapeX aims to overexpress the identified escapers in the disease model using viral vectors with the ambitious goal to rescue the sex-specific phenotype. Finally, we will combine allele-specific genomics and single-cell technology to explore if X-reactivation occurs in cardiac aging and disease and if such a novel disease mechanism further contributes to sex differences. EscapeX will elucidate new regulatory disease mechanisms and relevant therapeutic candidates, forming the basis of new sex-specific therapies.