NIH grant: DDX3X and post-transcriptional regulation of cardiac sex differences (1R01HL183984-01)

retained text

NIH grant 1R01HL183984-01: DDX3X and post-transcriptional regulation of cardiac sex differences
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Frank Leo Conlon. Award: $693182.
Start: 2026-07-10T00:00:00.
PROJECT SUMMARY
Congenital heart disease (CHD) is the most common type of congenital malformation [1, 2]. Many CHD
conditions exhibit bias based on sex [3-7]. However, there is a significant gap in our understanding of the
mechanisms behind these sex-specific differences. In a series of consecutive genetic screens in mice, we
identified the X-chromosome gene DEAD-Box Helicase 3 X-Linked (Ddx3x) as regulating male-female cardiac
sex differences [8]. DDX3X is expressed in cardiomyocytes and escapes X-inactivation in human hearts [9,
10]. Consistently, we demonstrated that in mice, DDX3X expression is reduced in Turner syndrome (XO)
hearts compared to wildtype females (XX) and increased in Klinefelter syndrome (XXY) hearts compared to
wildtype males (XY)[3, 8]. Clinical studies have shown that Ddx3x is associated with CHD in females but not
males [11-14]. To investigate the cardiac mechanisms associated with the cardiac sex differences related to
Ddx3x, we created a conditional allele for Ddx3x. We demonstrated that the deletion of Ddx3x in
cardiomyocytes (CM) results in embryonic death accompanied by cardiac desynchrony in female mice but not
in male mice by embryonic day (E) 11.5, suggesting that DDX3X plays a function in female cardiac excitation-
contraction coupling (ECC). We have gone on to define the endogenous cardiac DDX3X interactome and
showed that DDX3X interacts with proteins involved in mRNA translation. We further identified genes essential
in ECC as potential DDX3X target mRNAs. Based on our preliminary results, we hypothesize that DDX3X
regulates sex-specific mRNA translation that is critical for female cardiac excitation-contraction coupling.
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