Our long term goal is to understand, in molecular terms, how the heart muscle responds to stress. We have chosen to examine two systems, the SR calcium pump and the contractile protein myosin. Most of the efforts in this proposal are directed at an understanding of the genetic and phenotypic regulation of the SR pump. Our secondary goal is to contrast this regulation with that of the myosin heavy chain. The sarcoplasmic reticulum (SR) and the contractile protein myosin play important roles in myocardial performance. Recent studies indicate that the SR is altered in adaptive cardiac hypertrophy and failure. The molecular basis (genetic and phenotypic) for these changes is not understood. To increase our knowledge in this area we propose the following: 1) to characterize the cardiac muscle specific Ca ATPase and SR protein by molecular cloning analysis; 2) to determine the genetic regulation (transcriptional and post transcriptional controls) in normal, hypertrophied and atrophied myocardium; 3) to contrast the regulatory systems in each of the models for the coordinate and non coordinate control of the SR and myosin heavy chain (MHC) expression; 4) to isolate and characterize the complete gene for myocardial Ca++ ATPase; 5) to evaluate the regulatory sequences involved in Ca++ ATPase gene expression by introducing a cloned Ca++ ATPase gene into cardiac myocytes and muscle cells; 6) to provide a detailed functional analysis using mechanical and myothermal measurements on intact papillary muscles and biochemical measurements on isolated SR and to relate these to the genetic and phenotypic results obtained in the other aspects of the study. These studies will add to our understanding of the mechanisms involved in myocaridal adaptation to stress and the limitations placed on that adaptation.
