Contribution of ribosome specialization to the pathophysiology of muscular dystrophy

项目概要/摘要 横纹肌组织含有最高的线粒体含量和最大的已知蛋白质， 这对翻译机制提出了独特的挑战。肌肉组织特异性表达 一种旁系同源核糖体蛋白RLP 3L，与普遍存在的RPL 3大约80%相似， 对核糖体大亚基的形成至关重要。在肌肉中，RPL 3L替代RPL 3 但这如何改变核糖体的功能仍不清楚。而且这两 旁系同源证明了在肌肉适应、压力和 病理在营养不良的肌肉中，RPL 3L在核糖体中丢失而有利于RPL 3，但是对RPL 3的影响在核糖体中是不明显的。 肌肉功能下降是不了解的。最近的证据表明，核糖体可以 专门用来选择性地将某些基因翻译成蛋白质。此外，翻译控制 已经成为线粒体功能的一个新的调节层，线粒体功能在衰老早期下降， 肌肉萎缩症的病理学，在明显的表型之前。综上所述，我假设 营养不良肌肉中RPL 3L的缺失损害核糖体特化，从而导致失衡 线粒体和肌节蛋白质合成之间的联系， 进展肌营养不良症中肌肉特异性核糖体蛋白的拯救将提供 第一个证据证明核糖体特化在肌肉功能下降中的作用，并帮助指导 新疗法的设计。拟议的研究还将首次调查 糖皮质激素（营养不良的常见疗法）对肌肉核糖体特化的影响， 翻译选择性成功完成拟议的研究将揭示新的治疗方法 靶点以及慢性衰弱性疾病病理生理学的新机制。

Project Summary/Abstract Striated muscle tissue contains the highest mitochondrial content and the largest known proteins, which present unique challenges to the translational machinery. Muscle tissue specifically expresses a paralogous ribosomal protein, RLP3L, that is roughly 80% similar to the ubiquitous RPL3, and is essential to the formation of the large subunit of the ribosome. In muscle, RPL3L substitutes for RPL3 in the ribosome, but how this alters ribosome function remains unknown. Furthermore, these two paralogs demonstrate an inverse relationship under conditions of muscle adaptation, stress, and pathology. In dystrophic muscle, RPL3L is lost in favor of RPL3 in the ribosome, but the effects on muscle functional decline are not understood. Recent evidence suggests that ribosomes can specialize in order to selectively translate certain genes into proteins. Additionally, translation control has emerged as a novel layer of regulation for mitochondrial function, which declines early in the pathology of muscular dystrophy, prior to an overt phenotype. Taken together, I hypothesize that the loss of RPL3L in dystrophic muscle impairs ribosome specialization, thus contributing to an imbalance between mitochondrial and sarcomeric protein synthesis, exacerbating dystrophic disease progression. Rescue of the muscle specific ribosomal protein in muscular dystrophy will provide the first evidence for a role of ribosome specialization in muscle functional decline, and help guide the design of new therapeutics. The proposed studies will also, for the first time, investigate the impact of glucocorticoids (a common therapy for dystrophy) on muscle ribosome specialization and translational selectivity. Successful completion of the proposed studies will reveal new therapeutic targets as well novel mechanisms underlying the pathophysiology of chronic debilitating diseases.