Grant: Doctoral: Vanier Canada Graduate Scholarships

Congenital heart malformations (CHD) represent the single largest class of birth defects in humans with an estimated frequency of 1%. Moreover, they are the leading cause of mortality in infants under one year of age. Accumulating evidence points to a major role for genetic determinants in CHD. Despite remarkable progress over the past decade, CHD-causing gene mutations in humans have only been identified in a minority of cases. Proper function of the heart requires a formation of the four chambered heart in which blood flow is unidirectional. To ensure this, membranous walls - known as septa - separate the left and right atria and ventricles and specialized valves allow normal blood flow. Defects in septa and valves represent the major heart malformations in humans. Previously, we have used genetic and biochemical approaches to further define the role of newly discovered regulatory proteins in heart development and function, and their interactions with each other. In addition, several genes were identified and they were shown to be essential for heart formation and their studies provided the rationale to screen for a linkage between mutations in these genes and human CHD, which in turn identified them as disease causing genes. We have also developed new animal models of human heart disease that will be invaluable in pre-clinical studies aimed at identifying new preventive and therapeutic approaches to heart disease. The overall objectives of this proposal are to identify the genetic circuits that control the gene encoding atrial natriuretic peptide (ANP), the heart major secretory product, during embryonic and postnatal development; this in turn will shed light on the temporal and molecular events that pattern the embryonic heart and are essential for proper heart development. These studies will provide further insight in understanding the molecular basis of heart disease and will likely identify potential new candidates for CHD causing genes.