Grant: Project Grant

Birth defects of the heart, termed congenital heart disease (CHD) affect 1-2% of the population and represent the largest class of birth defects in human. CHD is the leading cause of death in infants during the first year of life and contribute to premature adult cardiovascular problems including with life threatening valve disease, heart failure and sudden death. Despite the evident socioeconomic burden, the diagnosis, treatment and care of CHD remain a major challenge. CHD is heritable, i.e. it 'runs in the family' but is it also influenced by genetic as well as environmental factors that remain undetermined. Moreover, many cardiac birth defects are degenerative in nature meaning they remain unsuspected (sub clinical) for many years and are detected at an advanced, often irreversible stage. At present, the genes that cause heart defects remain largely unknown and their identification will be greatly aided by the knowledge of the genes and circuits required for normal heart formation. During the past decade, our lab has proudly discovered several CHD causing genes including GATA4 and GATA5. Alterations in these genes are associated with several types of human CHD, including structural defects as well as rhythm abnormalities. Using our unique tools and animal models of human disease, we propose to identify the genetic and environmental factors that intersect with GATA proteins in heart formation. We believe that these efforts will uncover new potential CHD causing genes. We will also take advantage of our animal models of human disease to carry out studies important for understanding the degenerative nature of CHD, and that cannot be carried out in humans. The results of these studies will have an important impact on patient diagnosis and care. They will help prevent premature cardiac dysfunction and other cardiovascular complications in individuals with CHD or with a family history of CHD.