Subventions et des contributions :

Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2018-2019)

The contractile sarcomere of striated muscle is one of the most complex cellular protein assemblies, and we have studied the major components for decades. In contrast, the precise steps in the assembly of sarcomeres, as well as the homeostatic processes that maintain them during activity are poorly understood at the cellular or molecular level in any system. We know the components of muscle, but little about how they are assembled, or disassembled following damage. Quality control (QC) regulation of protein folding and homeostasis, as well as staged assembly of proteins in time and space, is critically important. Our program is to understand the molecular pathways that assemble and maintain the sarcomere, or allow repair or regeneration after damage. The focus of this proposal will be on the transcriptional control networks that regulate synthesis of sarcomere components, the posttranscriptional QC regulation of thick filament assembly, and the coordination between the two during normal development, as well as when the structure of the sarcomere is perturbed by genetic lesion. The aims are: (i) determine the molecular pathway of sarcomere patterning and assembly in skeletal and cardiac muscle, focusing on Protein Quality Control aspects; (ii) test predictions of this model i n vivo ; and (iii) use genetics to uncover novel components of this pathway. The zebrafish model system provides the power of genetics and genome editing technologies, as well as the ability to follow the process in a living transparent embryo in vivo . The structural and catalytic factors involved in the process of myogenesis are remarkably conserved, and we have been able to build upon our earlier work in C. elegans to provide key insights into these processes.