Ricardo A Demoya

Congenital heart diseases (CHDs) affect 1% of live births, with 25% resulting in a critical CHD, which requires surgical intervention within the first year of life. Hypoplastic left heart syndrome (HLHS), a critical CHD, is associated mainly with a hypoplastic left ventricle. Lack of a developed left ventricle means the body cannot supply oxygenated blood to the body and it will shut down without surgical reconstruction or transplantation. HLHS has been shown to be very heterogenous, meaning many different mutations can cause the same HLHS-like phenotypes. A genetic screen in mice found that a mutated Sin3A Associated Protein 130kDa (SAP130) was responsible for the hypoplastic left ventricle in one mouse line. This allele was shown to be hypomorphic, as when SAP130 KO mice were obtained and heterozygous (hetz) mice were crossed only hetz and wildtypes were found and peri-implantation lethality was reported.

This leads into my work which studies a zebrafish sap130a mutant allele. These fish present a small ventricle, similar to HLHS mice, ~50% of the time at 48 hours post fertilization (hpf). We have injected morpholinos and seen that knockdown of the Sin3a/HDAC complex components produces a small ventricle like the sap130a mutants. We hypothesize that the Sin3a/HDAC complex is influenced by loss of sap130a and that is why we get the small ventricle. We want to discover the transcriptional changes that lead to this and look for possible ways to rescue this phenotype by targeting dysregulated pathways. We are making mutants of these components to confirm the morphant phenotype and see if 100% small ventricle is possible in double or triple mutants. We have observed a functional deficit in all of these fish, supporting the idea that the changes to sap130a changed the cardiomyocyte cellular programing from the beginning of development.

The hope is that we will provide insight into the Sin3a/HDAC complex’s and/or sap130a’s involvement in cardiogenesis as well as possible targets for future treatment strategies for HLHS patients and other CHDs with chamber malformations.