The long-term goal of this project is to assess the feasibility of using engineered cardiac contractile proteins as the basis of gene therapy for cardiomyopathy. Various methods of global delivery of adenovirus and the ability of cardiac-specific promoters to limit transgene expression and ameliorate immune system activation in the hearts of adult mice and adult rabbits will also be assessed. In parallel, the functional consequences of mutations in cardiac troponin T, cardiac myosin regulatory light chains and cardiac myosin essential light chains will be assessed in quail myotubes. Promising constructs from the in vitro studies will be introduced into the hearts of wild type mice and rabbits, by recombinant adenoviruses driven by cardiac-specific promoters, to assess their effects on cardiac contractility in vivo. Again, the adaptive response of myocardial function in response to the transgene product will be followed, along with the persistence of expression. Finally, promising constructs from the wildtype in vivo studies will be introduced into the hearts of transgenic mice (possessing mutations inducing cardiomyopathy), and in rabbits with aortic-banded pressure-overload hypertrophy, to assess whether an improvement in cardiac contractility and an amelioration of the progression of disease can be realized.
