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

项目摘要/摘要 肌营养不良症(MD)是一组无法治愈的遗传性肌肉疾病，会导致进行性衰退 在受影响的患者中的肌肉力量、质量和功能。目前对MD的治疗在以下方面无效 防止肌肉退化，只是延缓功能障碍和死亡。营养不良的肌肉要抵抗 在退化过程中，它们必须能够持续合成肌肉修复所需的特定蛋白质， 收缩，并且功能的速度大于它们的退化。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，患者在 它们的早期阶段突出了对新疗法的需要，这些疗法侧重于延长再生能力 营养不良肌肉的功能。这一需求可以通过确定监管机制来满足 蛋白质合成的翻译调控。事实上，针对蛋白质翻译中的障碍代表着一种 使用新技术通过提高营养不良肌肉的修复能力来保护其功能的关键策略 增强修复特定蛋白质翻译的治疗学。在这项提案中，我们将研究 BEX1作为一种新的骨骼肌修复翻译效率调节因子。我们已经确定， 特性不佳的BEX1蛋白是在肌肉损伤或膜超载时诱导的，并且 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 BEX1通过以下途径增强肌肉再生和修复性生长所需蛋白质的翻译 与多tRNA合成酶复合体一起发挥作用，以调节翻译效率。我们将测试我们的 (1)研究BEX1在肌肉损伤和肌肉损伤中的作用。 体内再生。(2)确定BEX1在调节蛋白质合成的翻译调控中的作用。 (3)检测恢复BEX1水平对肌营养不良症的治疗潜力。这项工作将付诸实施 在费德里卡·阿克罗博士的实验室里，他是肌肉转录后调控的专家 肥大，在丹尼斯·古特里奇博士的共同监督下，丹尼斯·古特里奇博士是世界著名的骨骼肌专家 肌肉生成和肌肉萎缩的区域。随着这项工作的圆满完成，我们将拥有 阐明新的BEX1依赖机制在翻译过程中调节翻译效率的积极影响 肌肉修复和靶向BEX1促进肌肉再生和治疗潜力的确定 功能适用于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.