Noonan syndrome as a model to decipher the molecular mechanisms underlying human congenital heart defects

Noonan syndrome is a common cause of pediatric cardiomyopathies and congenital heart defects such as single ventricle defects. This grant proposal explores the impact of RAF1 as well as Noonan syndrome associated RAF1 mutations on early human cardiac development as a unique model to uncover the perturbed mechanisms that lead to single ventricle defects. Toward that goal, we will use human induced pluripotent stem (hiPSCs)-cardiac directed differentiation as an innovative model system to study single ventricle defects. hiPSC technology has emerged as an exciting paradigm to investigate the mechanisms underlying congenital heart defects because they are a patient-specific cell source and because of their capacity to generate cells of different stages of cardiac development. Therefore, we propose to differentiate hiPSCs with RAF1 genetic ablation as well as derived from Noonan syndrome patients towards a cardiac fate to identify and decipher at an unprecedented resolution the molecular mechanisms that are perturbed during cardiogenesis. Experiments derived from this proposal will allow a comprehensive in-depth interrogation of the molecular mechanisms deployed during human cardiogenesis and will identify perturbations in pivotal signaling, genetic and epigenetics pathways that could underlie single ventricle defects. Successful completion of our proposal will provide new knowledge regarding the transcriptional, signaling and protein networks controlling human cardiac development and will pave the way for
follow up studies to design therapies for children with single ventricle defects.