Contribution of ribosome specialization to the pathophysiology of muscular dystrophy

核糖体特化对肌营养不良症病理生理学的贡献

基本信息

批准号：
10685597
负责人：
YUAN WEN
金额：
$ 11.7万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-17 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685597
关键词：
ATP Synthesis Pathway Address Adult Biological Assay Cells Chronic Contractile Proteins Cytoplasm Data Disease Disease Progression Dose Drops Duchenne muscular dystrophy Equilibrium Exercise Failure Functional disorder Generations Genes Genetic Diseases Genetic Transcription Glucocorticoid Receptor Glucocorticoids Growth Hindlimb Image Impairment In Vitro Knock-out Knockout Mice Learning Maintenance Measurement Measures Mechanics Mediating Mentors Mentorship Mitochondria Mitochondrial Proteins Modeling Morphology Muscle Muscle Proteins Muscle function Muscular Atrophy Muscular Dystrophies Oxygen Consumption Pathogenesis Pathology Patients Performance Phase Phenotype Production Protein Biosynthesis Proteins Regulation Respiratory Diaphragm Ribosomal Proteins Ribosomes Role Running Skeletal Muscle Specificity Steroid therapy Steroids Stress Striated Muscles System Techniques Testing Time Tissues Training Transcript Translating Translations Up-Regulation Ventilator Yeasts career design effective therapy exercise training functional decline functional loss improved in vivo mdx mouse mitochondrial dysfunction mouse model muscle strength new therapeutic target novel novel therapeutics paralogous gene postnatal development protein expression restoration standard of care transcriptome sequencing

项目摘要

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.

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，这对转化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 RLP3L，与普遍存在的 RPL3 大约有 80% 相似，并且对于核糖体大亚基的形成至关重要。在肌肉中，RPL3L 替代 RPL3 存在于核糖体中，但是这如何改变核糖体功能仍然未知。此外，这两个旁系同源物在肌肉适应、压力和病理。在营养不良的肌肉中，核糖体中 RPL3L 丢失，取而代之的是 RPL3，但对肌肉功能衰退尚不清楚。最近的证据表明核糖体可以专门化以选择性地将某些基因翻译成蛋白质。此外，翻译控制已成为线粒体功能的新调控层，线粒体功能在早期就下降肌营养不良症的病理学，在明显的表型之前。综合起来，我假设营养不良性肌肉中 RPL3L 的缺失会损害核糖体特化，从而导致失衡线粒体和肌节蛋白质合成之间的相互作用，加剧营养不良性疾病进展。拯救肌营养不良症中的肌肉特异性核糖体蛋白将提供第一个证据证明核糖体特化在肌肉功能衰退中的作用，并有助于指导新疗法的设计。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）对肌肉核糖体特化和翻译选择性。成功完成拟议的研究将揭示新的治疗方法还针对慢性衰弱性疾病病理生理学的新机制。