Many processes in the heart depend upon post-transcriptional regulation of cardiac contractile gene expression. In disease states such as in cardiomyopathy, starvation induced atrophy, and during cardiac ischemia/reperfusion injury, protein turnover is significantly altered. Genetic dissection into the importance of maintaining proper sarcomere stoichiometry shows that missing or under-expressed elements lead to drastic structural changes in the contractile unit. Conversely, attempts to over-express many of the individual sarcomeric contractile proteins in the cardiomyocyte result in no observed change in the steady-state amounts of protein, and a conservation of sarcomere stoichiometry. Recent experiments have implicated the ubiquitin-mediated proteolytic pathway in the breakdown of contractile proteins. However, this has not been shown in the heart in vivo. Experiments are proposed in the Specific Aims that will address the in vivo post-transcriptional mechanisms by which the heart maintains a near crystalline array of sarcomere contractile proteins. These experiments will take advantage of a transgenic mouse model that already exists in the Sponsor's laboratory, a mouse model that over-expresses the cardiac sarcomere contractile protein ELC1V specifically in the heart. The hearts of these transgenic mice maintain sarcomere stoichiometry in the face of increased ELC1V transcripts, and so provide a useful reagent to study post-transcriptional regulation of gene expression in the mammalian heart. The long-term objective of this work is to understand what role post-transcriptional mechanisms play in regulating overall sarcomere stoichiometry in both the normal and diseased heart.
| Schwartzbauer, G; Robbins, J (2001) The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem 276:35786-93 |
