Utilizing Systems Genetics Approaches to Identify Novel Molecular Mechanisms in Cardiovascular Diseases

Despite the success of focused, reductionist approaches in characterizing the pathophysiology of cardiovascular diseases (CVDs), current estimates predict that 24 million deaths annually will be due to CVDs by 2030. Emphasizing the use of genetic variation in combination with mathematical modeling and integration of next generation –omics profiling technologies, systems genetics characterizes the flow of biological information in physiologic and pathologic states to allow investigators to understand the molecular interactions in a system. To assess the feasibility of systems genetics based methodologies in identifying novel interactions that contribute to CVD pathology I have used a combination of animal and cell culture models to recapitulate key processes involved in two CVDs: atherosclerosis and congestive heart failure.Atherosclerosis, a systemic disorder characterized by the narrowing of arteries is the underlying cause of the majority of clinical cardiovascular events. Formation of the atherosclerotic plaque is driven by chronic endothelial activation from exposure to oxidized phospholipids that accumulate within the vessel wall. Using systems approaches we have identified miRs-21-3p and -27a-5p as novel regulators of NF-κB signaling, a crucial pathway in mediating endothelial activation. Congestive heart failure (CHF) is a CVD that develops in part as a complication of atherosclerosis that is characterized by the inability of the heart to pump blood. Using a novel genetic screening panel in mouse in combination with system based approaches, I have identified and characterized the function of numerous novel genes that modulate CHF phenotypes such as cardiac fibrosis (Abcc6), left ventricular mass (Myh14) and cardiac hypertrophy (Adamts2)