Mutations in sarcomere genes like MYBPC3 and ACTC1 cause both LVNC and hypertrophic cardiomyopathy (HCM). Using humanized mouse models with various MYBPC3 mutations linked to mixed HCM and LVNC phenotypes, we identified shared molecular mechanisms. Mutant mice exhibit hypertrabeculation at postnatal day 1 (P1), progressing to hypertrophy by P7, accompanied by defective cardiomyocyte metabolic maturation and increased proliferation dynamics. Additionally, whole-genome sequencing in HCM families lacking sarcomere gene mutations aims to uncover non-sarcomere candidate genes, which we model in mice and hiPSCs to explore their roles in HCM and inheritance patterns.
Congenital heart defects (CHD) and cardiomyopathies involve impaired ventricular growth, developmental delays, and defects in ventricular wall maturation. Our studies show that disruptions in key signaling pathways alter cellular processes like proliferation, differentiation, and tissue patterning, leading to structural and functional abnormalities. GWAS has linked SNPs in genes related to cytoskeletal organization, arterial specification, secretion, β-catenin signaling, and proliferation with ventricular trabecular complexity and reduced cardiac risk (PMID: 32814899, 39567769). Loss of genes like MECOM, TM2D1, GOSR2, and COG5 results in severe cardiac defects, and we are characterizing their molecular underpinnings.
Development of the placenta begins alongside pregnancy, requiring synchronization with fetal growth to adequately support gestation. Intriguingly, development of the placenta and fetal heart progress in tandem, a phenomenon known as the placenta-heart axis. While the genetics of heart development has garnered significant attention, the parallel development of the placenta and heart has been relatively overlooked. Considering that both organs may share crucial developmental pathways and genetic networks, defects in these common genes could potentially disrupt both heart and placental morphogenesis. Mouse studies show that placental gene dysfunction can cause secondary heart defects, highlighting the importance of this axis in CHD. We have shown that GPR126, a putative NOTCH effector in the embryonic endocardium, plays an essential role in the placenta (PMID: 34767447). Our goal is to uncover how the placenta and heart communicate at cellular and molecular levels to ensure normal development. As part of an international Leducq consortium, we will use integrated meta-analysis of scRNA-seq, GWAS, DNA methylation data, and lethal mouse mutant databases, to identify genes critical to both organs, either independently or jointly.
Current projects
Title: LEDUCQ INTERNATIONAL NETWORK: THE PLACENTA IN MATERNAL AND FETAL CARDIOVASCULAR HEALTH AND DISEASE (The PlacHeart Network). Agency: Leducq Foundation. Role: Principal Investigator and partner of an International Network. Funds: $1,120,157.49. Five years. Awarded: June 2024. Project Period: January 2025-December 2030.
Title: Novel genetic and mechanistic studies of hypertrophic cardiomyopathy (CARDIOGENOMICS). Agency: Fundación La Caixa. Project Period: 01/09/2023 – 31/08/2026. Role: Coordinator. Funds: €998,798.62 (€542,461.80 for CNIC).
Title: Molecular basis of cardiomyocyte maturation: Implications for congenital heart disease and cardiomyopathy (PID2022-136942OB-I00). Agency: MINISTERIO DE CIENCIA E INNOVACION- Proyectos de Generación de Conocimiento 2022. Project Period: 01/09/2023 – 31/08/2026. Funds: €406,250.00€.
Title: CIBER Cardiovascular (CB16/11/00399). Agency: Instituto de Salud Carlos III. Project Period: 2017 –open end. Role: Principal Investigator. Funds: € 58,000.00 per year.
