Research in our laboratory has a common aim - to understand congenital heart defects. Congenital heart defects are the #1 birth defect, as unfortunately each year over 30,000 babies in USA are born with congenital heart defects (www.nhlbi.nih.gov). Significantly, the heart is the first organ to develop in the mammalian embryo and remarkably it functions even before it is fully formed. We focus on the pathogenesis of conotruncal and valvular heart defects, which result from a failure of the aorta and pulmonary trunks to become separate blood vessels and associated outflow tract endocardial cushion/valvular remodeling anomalies. Lack of outflow tract septation often results in lethality secondary to respiratory failure as there is inappropriate mixing of the oxygenated and de-oxygenated circulations postnatally. Similarly, valvular insufficiency can also result in postnatal lethality due to an inability to maintain a unidirectional bloodflow. Using both transgenic over-expressor and targeted systemic and Cre/loxP conditional knockout mice models, we are investigating when cardiac development first goes wrong in utero, identifying the cell lineages responsible, genetically ablating them using diphtheria toxin-A and then attempting to correct the various heart malformations. For instance, we generated a Sodium calcium exchanger knockout mouse that fails to initiate a heartbeat (being used to determination form vs. function and role of bloodflow during vascular remodeling); a Pax3 transcription factor conditional knockout (being used to assess cell autonomous requirement of the cardiac neural crest cells during outflow tract septation); and Periostin knockout, promoter indicator and Cre-recombinase expressing mice lines (being used to determine the role of secreted Periostin adhesion protein during endocardial cushion and valve leaflet development, as well as the establishment of the embryonic heart’s skeleton). If these congenital cardiovascular defects can be prevented and/or nullified in genetically-defined mouse mutant models – we then hope to apply the knowledge gained to help engineer potential treatments for pediatric patients.