Leslie Leinwand

Research Profile:

Muscle contraction requires that numerous motor and structural proteins assemble into the highly ordered structure of the sarcomere. Perturbations in the interactions of these proteins by mutation cause a severe genetic heart disease, hypertrophic cardiomyopathy. This is the leading cause of sudden death in young athletes. We have created transgenic mouse models for this disease by introducing mutations in cardiac myosin heavy chains and troponin T, into mice. Myosin is the molecular motor of myosin, and troponin T is a regulatory molecule that is part of a Ca2+ sensing complex in the sarcomere. Patients with myosin mutations have frequent enlargement in their hearts and variable sudden death while patients with troponin T mutations have little or no enlargement and a very high incidence of sudden death. Mice expressing these mutations have given us insight into these different clinical outcomes. Hearts from mice with the troponin mutations are not enlarged because there are fewer heart muscle cells present and those that are there, are smaller. We are currently defining the biochemical and cellular defects in the mutation myosin and troponin T molecules. These and other mice we have generated also present asubstrate on which to test various RNA-mediated genetic therapies. These include hammerhead ribozhymes, tRNA suppression for nonsense mutations, and exon skipping. As part of a collaborative effort in Cardiology at UCHSC, we are exploring the molecular mechanisms leading to human heart failure. These studies involve defining changes in mRNA and protein expression in different states. This line of research complements the work in animal models of cardic disease. Other research in the laboratory involves a genetic investigation into the role of myosin genes in mouse skeletal muscle. There are seven distinct genes that are expressed in temporally and spatially distinct manners. To determine the role that individual members of the gene family play in muscle development and function, we have used homologous recombination to inactivate the two major adult skeletal myosin heavy chain genes in the mouse. These mice have significant defects, and most interestingly, the defects are quite distinct between the two “knockout” strains. In one case, an adjacent myosin heavy chain gene has been activated to compensate for the loss of its neighbor. Under investigation is the molecular mechanism whereby there is “cross talk” among members of this multigene family.