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

项目总结/摘要 肌营养不良症（MD）是一组无法治愈的遗传性肌肉疾病，导致进行性衰退 受影响患者的肌肉强度、质量和功能。目前对MD的治疗无效， 防止肌肉退化，只是推迟功能障碍和死亡。让营养不良的肌肉抵抗 退化，他们必须能够不断合成肌肉修复所需的特定蛋白质， 收缩，并以大于其降解的速率起作用。虽然许多治疗方法都不成功， 专注于治疗这些疾病的潜在遗传缺陷， 它们的早期阶段突出了对新疗法的需求，这些疗法专注于延长再生能力， 以及营养不良肌肉的功能。这一需要可以通过确定监管机制来满足。 蛋白质合成的翻译控制。事实上，靶向蛋白质翻译中的损伤代表了 通过使用新的方法改善其修复能力来保护营养不良肌肉功能的关键策略 增强修复特异性蛋白质翻译的治疗剂。在本建议中，我们将研究 BEX 1作为骨骼肌修复中翻译效率的新调节剂。我们已经确定， 表征不佳的蛋白BEX 1响应于肌肉损伤或膜过载而被诱导， 在这些修复诱导条件下，它与蛋白质翻译所需的分子相互作用。我们假设 BEX 1通过以下方式增强肌肉再生和修复性生长所需蛋白质的翻译 与多tRNA合成酶复合物一起发挥作用以介导翻译效率。我们将测试我们的 通过执行以下目标来验证这一假说：（1）描述BEX 1在肌肉损伤中的作用， 体内再生(2)确定BEX 1在蛋白质合成的翻译调控中的作用。 (3)测试恢复BEX 1水平在肌营养不良症中的治疗潜力。这项工作将由 在Federica Accornero博士的实验室里， 肥大，在世界著名的骨骼肌专家丹尼斯·古特雷斯博士的共同监督下， 肌肉发生和肌肉萎缩的区域。随着这项工作的顺利完成，我们将有 阐明新的BEX 1依赖性机制的积极影响，该机制调节翻译效率， 肌肉修复和确定靶向BEX 1以改善肌肉再生的治疗潜力， 功能为MD患者。

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.