Approximately 7.6 m Americans currently suffer the burden of myocardial infarction (MI) and there are ~1 million new and recurrent MIs each year resulting in immediate death in some individuals and a predisposition to heart failure (HF) in survivors. Given that necrosis is the major type of cell death in the heart during MI and drives the gradual loss of cells associated with the progression of HF, defining the molecular mechanisms underlying necrosis will offer novel treatment strategies for cardiovascular disease and numerous other death-driven disorders. The current proposal is designed to define the role of N- ethylmaleimide sensitive factor (NSF gene) in programmed necrosis. NSF encodes an ATPase that is required for SNARE-mediated membrane fusion events. Here we provide preliminary data that NSF plays a significant role in membrane rupture and programmed necrosis. This proposal will examine the centrality of NSF in cellular pathways involved in programmed necrosis and using genetic gain- and loss-of-function strategies evaluate the contribution of NSF to myocardial ischemia-reperfusion injury and the progression of heart failure resulting from diverse etiologies. The ultimate goal of these studies is to develop novel therapeutic strategies with translational potential.
Approximately 7.6 m Americans currently suffer the burden of myocardial infarction (MI, heart attack) and there are ~1 million new and recurrent MIs each year resulting in immediate death in some individuals and a predisposition to heart failure (HF) in survivors. Further, the incidence of HF is projected to increase by 25% over the next 20 years with a projected cost of ~$70 billion representing a substantial health and economic burden on the US. Given that necrosis is the major type of cell death in the heart during MI and drives the gradual loss of cells associated with the progression of HF, defining the molecular mechanisms underlying necrosis may offer novel treatment strategies for cardiovascular disease and numerous other death-driven disorders. This project examines a novel molecular mechanism driving pathogenic cell death with the hope of developing novel therapeutics to treat heart disease.
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