The role of BEX1 in translational control of muscle regeneration and reparative growth

项目总结/文摘

Project Summary/Abstract Muscular Dystrophy (MD) is a group of incurable, genetic, muscle disorders that result in progressive declines in muscle strength, mass, and function among affected patients. Current treatments for MD are ineffective at preventing muscle degeneration and merely postpone dysfunction and death. For dystrophic muscles to resist degeneration, they must be able to continuously synthesize specific proteins required for muscle repair, contraction, and function at rates greater than their degradation. While many therapies have unsuccessfully focused on treating the underlying genetic defects of these diseases, the preserved functionality of patients in their early stages highlights the need for new therapeutics that focus on prolonging the regenerative capacity and functionality of dystrophic muscles. This need can be met by identifying mechanisms regulating translational control of protein synthesis. Indeed, targeting impairments in protein translation represents a critical strategy to preserve dystrophic muscle functionally by improving its repair capabilities using novel therapeutics that enhance the translation of repair specific proteins. In this proposal, we will examine the role of BEX1 as a novel regulator of translation efficiency in repairing skeletal muscles. We have identified that the poorly characterized protein BEX1 is induced in response to muscle damage or membrane overload and that in these repair-inducing conditions, it interacts with molecules required for protein translation. We hypothesize that BEX1 enhances the translation of proteins required for muscle regeneration and reparative growth by functioning with the multi-tRNA synthetase complex to mediate translational efficiency. We will test our hypothesis by carrying out the following aims: (1) To characterize the role of BEX1 in muscle injury and regeneration in vivo. (2) To determine the role of BEX1 in regulating translational control of protein synthesis. (3) To test the therapeutic potential of restoring BEX1 levels in muscular dystrophy. This work will be carried out in the laboratory of Dr. Federica Accornero, an expert on the post-transcriptional regulation of muscle hypertrophy, under the co-supervision of Dr. Denis Guttridge, a world-renowned skeletal muscle expert in the areas of myogenesis and muscle atrophy. With the successful completion of this work, we will have the positive impact of elucidating novel BEX1-dependent mechanisms that regulate translational efficacy during muscle repair and determining the therapeutic potential of targeting BEX1 to improve muscle regeneration and function for patients with MD.