Grant: Project Grant

Heart failure afflicts 350,000 Canadians and contributes to 10% of deaths in Canada. Despite significant research and treatment advances, heart failure morbidity and mortality will increase 3-fold by 2050. Among the most common causes of heart failure is ischemic heart disease, which is increasing worldwide. Myofilament proteins provide the mechanical basis for heart muscle contraction. We were the first to show reducing the myofilament-associated protein 'CapZ' in the heart stimulates myofilament activity and regulates signaling molecules that drive heart failure. We also discovered that TG mice with 20% less cardiac CapZ are protected against heart attacks. To translate our novel findings into a clinically relevant tool we designed unique CapZ interfering peptides. Our pilot studies show decreasing CapZ with our peptides stops heart muscle dysfunction associated with heart attacks. We have also identified changes in CapZ proteins in samples from human and veterinary heart failure patients. Therefore we identified CapZ as a novel therapeutic target to protect against post-heart attack damage. Our objectives are: 1. determine how altered CapZ affects hearts under stress; and 2. develop a clinically viable approach to target CapZ to protect hearts. To address these objectives we will test the ability of our unique CapZ interfering peptides to protect against injury associated with heart attacks and heart failure. These innovative ideas can only be tested in our laboratory as we are the only group to possess both the TG mice and CapZ interfering peptides, as well as the expertise to cover the full range of studies. Our research will advance our understanding of the role CapZ has in the heart's response to disease and translate promising research into an applicable outcome.