Grant: Project Grant

Muscular dystrophies are genetic disorders that afflict more than 50,000 Canadians and for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset form of muscular dystrophy that is found worldwide, but that is more frequent in the French Canadian and Jewish populations. OPMD is a disorder of skeletal muscle cells that is primarily associated with eyelids drooping, swallowing difficulties, and proximal limb weakness. The underlying genetic defects of OPMD are small GCG insertions in the PABPN1 gene that expands the amino terminal polyalanine tract of PABPN1 from 10 to 12-17 residues. To date, the underlying mechanism by which short GCG insertions in the PABPN1 gene causes OPMD remains completely unknown. Furthermore, limited knowledge exists about the cellular functions of PABPN1. The objective of this application is therefore to provide better understanding about the mechanistic function of PABPN1. The central hypothesis of our research project, which is based on our preliminary findings, is that PABPN1 functions in a specialized nuclear pathway of gene regulation. We propose to characterize this novel PABPN1 function using various cultured human cell lines, including muscle cells, which allow for detailed mechanistic studies of human PABPN1. In addition to shedding new, fundamental knowledge into the role of PABPN1 in gene regulation, our studies are expected to further the understanding into the molecular basis of OPMD. As such, our studies may ultimately address why OPMD is restricted to specific skeletal muscles, and therefore, lay the groundwork for developing much needed therapies.