Ricerc@Sapienza

Heart development is a complex process that starts with the generation a heart tube that then loops and forms septs to accomplish the embryo¿s systemic and pulmonary circulation. Damage at any point during the primary morphogenetic process results in Congenital Heart Defects (CHD), which in humans have a large incidence (6-8 every 1000 live births). Ventricular Septum Defect (VSD) accounts for 40% of CHDs. Unrepaired VSDs cause ventricular dilation leading to heart failure, pulmonary arterial hypertension, arrhythmias and ultimately decreased life expectancy. Despite VSDs are quite common, the etiology and pathogenesis of these disorders are largely unknown because lacks the understanding of the underlying molecular and cellular mechanisms.
cAMP is a cyclic nucleotide functioning as second messenger having a fundamental role in a plethora of signaling cascades. Its cellular level is fine-tuned by phosphodiesterases (PDEs) hydrolytic enzymes.
Among PDEs, PDE2A is unique because the knockout mouse model (Pde2A-/-) is embryonically lethal. Pde2A-/- embryos display nuchal edema, a defect frequently associated to CHD, anemia, diffuse hemorrhages and an extremely reduced liver size.
We recently demonstrated a direct relationship between Pde2A impairment and onset of mouse congenital heart defects. These defects are associated with the increase of cAMP concentration, highlighting a novel role for this second messenger in cardiac development regulation. We hypothesized that PDE2A might have an essential role in heart development by regulating the dimension of the compartmentalized pool of cAMP that affects the expression of genes controlling heart morphogenesis and function.
In the present application we will dissect molecular pathways modulated by cAMP in CHD. We propose to explore whether pharmacological treatments that lower cAMP levels/function might rescue heart defects in Pde2A deficient mice and whether the defects are cardiac tissue specific.