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Deciphering the roles of FXR1 in health and myopathy

解读 FXR1 在健康和肌病中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘