Grant: Project Grant

Congenital heart defects are observed in 0.9% of newborns and are responsible for an estimated 10% of all stillbirths. Abnormal development of heart valves and septa occurs in 20-30% of cardiac malformations. Current research suggests that valve disease in adults can arise from underlying congenital defects. Since valve disease, resulting in failure of valve leaflets to close properly, affects over 3% of the population in North America, improvements in managing of valve disorders can have a major health impact. A better understanding of the molecular mechanisms underlying congenital valve defects will provide options to correct valve disorders in children and provide opportunities to reverse valve disease in adults. Our laboratory is interested in the mechanisms through which genes are regulated in heart valve development, using the mouse embryo as our model. Our work has focused on a protein, called SOX9, which regulates how genes are turned on and off in cells. In heart valves, SOX9 is required for normal development but how it does this is unknown. Our hypothesis is that SOX9 controls cascades of genes that dynamically change at different stages during valve development. We believe that SOX9 functions are dependent on the expression of proteins, called co-factors, that function with SOX9 to control genes. To address this hypothesis, we are using whole genome sequencing methods to identify all of the genes that are regulated by SOX9 in mouse embryonic valves throughout development. In our first aim, we will examine how SOX9 regulates DNA structure. In the second aim, we will look at how co-factors interact with SOX9 to regulated gene expression in embryonic valves. In the third aim, we will examine how many cell types are present in embryonic valves. By providing insight into the normal biology of valves development, our work may identify new targets that can be developed for therapeutic applications in valve repair strategies.