On the Molecular Basis of Monogenic Human Hypertrophic and Dilated Cardiomyopathies

After 40 years of developing and utilizing assays to understand the molecular basis of energy transduction by the myosin family of molecular motors, all members of my laboratory are now focused on understanding the underlying biochemical and biophysical bases of human hypertrophic (HCM) and dilated (DCM) cardiomyopathies. HCM and DCM are most often a result of single missense mutations in one of several sarcomeric proteins, the sarcomere being the fundamental contractile unit of the cardiomyocyte. Associated with HCM and DCM worldwide are heart failure, arrhythmias, and sudden cardiac death at any age. We are using in vitro molecular studies of biochemically reconstituted human sarcomeric protein complexes to lay the foundation for understanding the effects of HCM- and DCM-causing mutations on power generation by the contractile apparatus of the sarcomere. With such a detailed understanding at the molecular level, one should be able to exquisitely design and screen for appropriate small molecule therapies that are desperately needed for treatment of these diseases.