Grant: Operating Grant

In humans, congenital heart malformations represent the single largest class of birth defects with an estimated frequency of 4-5 percent of live births. Defects of the septa and valves account for the majority of congenital heart disease. Thanks to advances in surgical repairs, over 1 million adults in North America are living with CHD but face a lifetime of problems including arrhythmias, ventricular dysfunction, one or more re-operations and premature death from myocardial infarction, sudden death or stroke. Late referral and intervention have a deleterious effect on long term and event free survival. For example, the more subtle defects like atrial septal defects or subclinical valve defects, cause progressive degeneration leading to early adult requirement for valve replacement and other major interventions. Even benign defects like persistent foramen ovale , a form of ASD affecting 25 per cent of the population are associated with significant cardiovascular risks including a 3 to 6 fold increase in stroke, the major cause of morbidity in industrialized countries. Identification of the genes responsible for CHD will enhance early diagnosis, care and follow up of patients which will significantly decrease cardiovascular complications. It is the objective of the present grant proposal to identify the regulatory circuits and genes essential for valve and septal formation and test the consequences of their dysfunction on heart development using molecular genetics and biochemical studies. The experiments proposed are likely to identify potential disease causing genes and to produce animal models of human birth defects that will accelerate development of preventive and therapeutic approaches of heart disease.