Deciphering the roles of FXR1 in health and myopathy

解读 FXR1 在健康和肌病中的作用

• 批准号: 10888822
• 负责人: Carol C Gregorio
• 金额: $ 63.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10888822
• 关键词: Affect; Animal Model; Animal Muscular Dystrophy; Architecture; Area; Attenuated; Binding; Biology; Canis familiaris; Cardiac; Cell model; Complex; Coupling; Data; Defect; Dilated Cardiomyopathy; Disease; Disease Progression; Duchenne cardiomyopathy; Duchenne muscular dystrophy; Dystrophin; FMR1; FXR1 gene; Facioscapulohumeral Muscular Dystrophy; Family; Family suidae; Fragile X Syndrome; Functional disorder; Gene Expression Regulation; Genetic Transcription; Goals; Health; Human; Inherited; Investigation; Knock-out; Knockout Mice; Laboratories; Life; Link; Messenger RNA; Metabolism; Modeling; Molecular; Multiminicore disease; Mus; Muscle; Muscle Cells; Muscle Contraction; Muscle Development; Muscle function; Muscle relaxation phase; Myocardium; Myopathy; Myosin Regulatory Light Chains; Myotonic Dystrophy; Pathogenesis; Pathology; Perinatal mortality demographics; Phosphorylation; Physiological; Play; Post-Transcriptional Regulation; Process; Property; Proteins; Proteome; Psyche structure; RNA; RNA-Binding Proteins; Rattus; Regulation; Relaxation; Research; Rodent Model; Role; Skeletal Muscle; Striated Muscles; Structure; Testing; Therapeutic; Tissue Model; Tissues; Utrophin; Work; autism spectrum disorder; disability; experimental study; functional improvement; gene therapy; human model; human tissue; improved; in vivo; insight; interdisciplinary approach; knockout animal; mRNA Expression; mRNA Stability; mRNA Translation; mouse model; muscular dystrophy mouse model; muscular structure; novel; novel therapeutics; posttranscriptional; prevent; protein expression; response; single molecule; skeletal; therapeutic RNA; tool; transcriptome

PROJECT SUMMARY/ABSTRACT The mechanism whereby RNA-binding proteins impact muscle function and disease progression is still largely unknown. Fragile X-related protein 1 (FXR1), an RNA-binding protein, is multi-functional and plays a role in regulating the temporal and spatial expression of RNAs in myocytes. It is becoming increasingly evident that FXR1 is essential for normal muscle function and is associated with both human cardiac and skeletal myopathies. Although global knockout of Fxr1 in mice results in perinatal lethality with cardiac and skeletal muscle defects, little is known regarding the fundamental mechanistic role(s) of FXR1. We discovered that FXR1 interacts with, and post-transcriptionally regulates, mRNAs that encode proteins essential for excitation-contraction coupling, including components that regulate phosphorylation of the myosin regulatory light chain (RLC). We also identified an interaction between FXR1 and the mRNA that encodes utrophin, a protein that can functionally substitute for the loss of dystrophin in Duchenne Muscular Dystrophy. Our extensive preliminary data, and data from others, reveal that FXR1 protein levels are significantly reduced in human DMD myocytes as well as in all DMD models tested including those from canine, pig, mouse and rat. Remarkably, restoring FXR1 levels in three different mouse models of DMD attenuates disease progression, resulting in structural and functional improvements in both cardiac and skeletal muscle. Utrophin expression is also enhanced in DMD mice in response to increased FXR1 levels. Thus, we hypothesize that FXR1 specifically regulates cellular components that are critical for proper muscle function and alterations in FXR1 levels/function contribute to disease progression, particularly in DMD. We propose a global, unbiased and multidisciplinary approach from single molecule to in vivo studies, including the use of human tissue, to allow us to accomplish three Specific Aims focused on determining the basic physiological function of a Fragile X protein and the role it plays in muscle pathogenesis. In addition, we will be among the first groups to assess gene-therapy strategies to prevent muscle dysfunction in DMD-rats (a model which closely resembles human DMD). We predict these discoveries will facilitate a unique RNA-level therapeutic approach to ameliorate muscle disease progression.

项目概要/摘要 RNA结合蛋白影响肌肉功能和疾病进展的机制仍不清楚 很大程度上不为人知。脆性 X 相关蛋白 1 (FXR1) 是一种 RNA 结合蛋白，具有多功能性，在 调节肌细胞中 RNA 的时间和空间表达。越来越明显的是 FXR1 对于正常肌肉功能至关重要，并且与人类心脏和骨骼肌病有关。 尽管小鼠体内 Fxr1 的整体敲除会导致围产期死亡并伴有心肌和骨骼肌缺陷， 关于 FXR1 的基本机制作用知之甚少。我们发现 FXR1 与以下相互作用： 并进行转录后调节，编码兴奋-收缩耦合所必需的蛋白质的 mRNA， 包括调节肌球蛋白调节轻链 (RLC) 磷酸化的成分。我们还确定了 FXR1 与编码 utropin 的 mRNA 之间的相互作用，utropin 是一种可以在功能上替代 杜氏肌营养不良症中肌营养不良蛋白的丢失。我们广泛的初步数据以及其他人的数据， 揭示人类 DMD 肌细胞以及所有 DMD 模型中 FXR1 蛋白水平显着降低 测试对象包括犬、猪、小鼠和大鼠。值得注意的是，在三种不同的情况下恢复 FXR1 电平 DMD 小鼠模型可减缓疾病进展，从而导致结构和功能改善 心肌和骨骼肌。 DMD 小鼠中 Utropin 的表达也随着增加的 FXR1 级别。因此，我们假设 FXR1 特异性调节对细胞功能至关重要的细胞成分。 适当的肌肉功能和 FXR1 水平/功能的改变有助于疾病进展，特别是在 DMD。我们提出了从单分子到体内研究的全球性、公正性和多学科方法， 包括使用人体组织，使我们能够实现三个具体目标，重点是确定 脆性 X 蛋白的基本生理功能及其在肌肉发病机制中的作用。此外，我们 将是第一批评估预防 DMD 大鼠肌肉功能障碍的基因治疗策略的小组之一（a 与人类 DMD 非常相似的模型）。我们预测这些发现将促进独特的 RNA 水平 改善肌肉疾病进展的治疗方法。