Grant: Operating Grant

Heart/cardiac disease is a broad health concern for all post industrial societies. A consistent feature to the many variants of cardiac illness is inappropriate growth of heart muscle, commonly referred to as cardiac hypertrophy. The initial expansion in the size of the heart is often a beneficial response to an external stress (i.e. increased blood pressure) or damage to existing heart muscle, yet the muscle growth quickly leads to a loss of function, increasing the likelihood of adverse events such as heart failure. Cardiac hypertrophy itself is derived from an excessive increase in the size of individual heart muscle cells and numerous individual genes and proteins have been implicated in driving this process forward. Nevertheless, while these studies have greatly increased our understanding of how the heart muscle cell responds or accommodates growth, few studies have examined what factors inside the cell integrate various growth signals or control the restructuring process. Here, we are examining whether cell death genes/proteins are required for this critical remodeling of heart muscle cells. These proteins, referred to as caspases, are critical regulators of cell destruction or cell suicide (the scientific term is apoptosis) and act by targeting and destroying other cell proteins. Our preliminary observations indicate that these 'cell death' proteins become active during cardiac hypertrophy and can induce growth of a heart muscle cell without causing the destruction of the cell. Importantly, our observations suggest that caspases may represent viable and tractable targets for treating and limiting the pathology associated with cardiac hypertrophy. The current research plan will build on this exciting area of investigation and provide the necessary information for designing and implementing appropriate pre-clinical models for the treatment of cardiac hypertrophy.