Mechanisms of Skeletal Muscle Pathogenesis in Myotonic Dystrophy Type 1

1 型强直性肌营养不良的骨骼肌发病机制

• 批准号: 10716746
• 负责人: Thomas A Cooper
• 金额: $ 54.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716746
• 关键词: 3' Untranslated Regions; Adult; Affect; Alleles; Alternative Splicing; Blood specimen; CUG repeat; Characteristics; Clinical; Disease; Disease Progression; Embryo; Etiology; Exons; Family; Family member; Fetal Proteins; Foundations; Frequencies; Genes; Genetic; Genetic Transcription; Goals; Histopathology; Human; In Vitro; Individual; Knock-out; Link; LoxP-flanked allele; Messenger RNA; Modeling; Molecular; Mus; Muscle; Muscular Atrophy; Muscular Dystrophies; Mutation; Myopathy; Myotonic Dystrophy; Myotonic dystrophy type 1; Natural regeneration; Newborn Infant; Nuclear; Nuclear RNA; Pathogenesis; Pathogenicity; Pathology; Pattern; Phenotype; Physiological; Play; Prevalence Study; Protein Isoforms; Proteins; RNA; RNA Processing; RNA Splicing; RNA-Binding Proteins; Regulation; Role; Severity of illness; Skeletal Muscle; System; Tissues; Toxic effect; Transgenic Mice; Translations; United States; Up-Regulation; Work; autosome; combinatorial; gain of function; in vivo; knock-down; loss of function; mRNA Translation; mortality; mouse model; mutant; postnatal development; response; skeletal muscle weakness; small hairpin RNA; targeted treatment; wasting

Project Summary Myotonic dystrophy is the second most common cause of muscular dystrophy and the most common cause of adult onset muscular dystrophy. The primary cause of disease mortality is progressive skeletal muscle weakness and wasting. The long term goal of this project is to determine the mechanisms that cause skeletal muscle pathogenesis in myotonic dystrophy type 1 (DM1). DM1 is an autosomal dominant disease caused by a CTG repeat expansion in the 3’ untranslated region of the DMPK gene. The molecular basis for the disease is a toxic gain of function of the RNA containing expanded CUG repeats (CUGexp RNA) that is transcribed from the mutant allele. CUGexp RNA accumulates in nuclear RNA foci and causes loss of function of Muscleblind like (MBNL) RNA binding proteins that are sequestered on CUGexp RNA within the nuclear foci. CUGexp RNA also induces upregulation of CELF1 protein that has been shown to be toxic to skeletal muscle. MBNL and CELF1 proteins regulate alternative splicing transitions of a large number of genes during skeletal muscle postnatal development. Their altered functions in DM1 skeletal muscle causes misregulated alternative splicing and inappropriate expression of fetal protein isoforms in adult skeletal muscle that leads to disease features. While the basis for MBNL loss of function has been established, the mechanisms causing CELF1 upregulation in skeletal muscle are unknown. We find that Mbnl1/Mbnl2 double knockout in adult mouse skeletal muscle results in CELF1 protein upregulation, indicating a mechanistic link between MBNL loss of function and increased CELF1 activity. We also established a transgenic mouse model for DM1 in which skeletal muscle specific expression of a human DMPK mRNA containing expanded CUG repeats reproduces DM1 features including CELF1 upregulation. The goals of this proposal are to determine the molecular mechanisms of CELF1 upregulation in response to Mbnl1/Mbnl2 double knockout and expression of the toxic CUGexp RNA and to determine the contributions of CELF1 upregulation to skeletal muscle pathogenesis caused by MBNL loss of function and CUGexp RNA.

项目总结