Establishing an FSHD-like mouse for therapeutic development

建立类 FSHD 小鼠用于治疗开发

• 批准号: 9167305
• 负责人: Peter L Jones
• 金额: $ 1.74万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167305
• 关键词: Address; Adult; Affect; Alternative Splicing; Animal Model; Apoptosis; Binding; Biological Markers; Breathing; Canis familiaris; Characteristics; Child; Chromatin Structure; Clinical; Comb animal structure; D4Z4; DNA; DNA Binding; DNA Methylation; DNA-Binding Proteins; Data; Development; Disease; Disease Progression; Elements; Engineering; Environmental Risk Factor; Epigenetic Process; Event; Exhibits; Facioscapulohumeral Muscular Dystrophy; Female; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Structure; Generations; Genes; Genetic; Genetic Recombination; Goals; Hair; Hand Strength; Histopathology; Homeodomain Proteins; Hormones; Human; In Vitro; Inflammatory Response; Lead; Life; Live Birth; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular Profiling; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Dystrophies; Myopathy; Nonsense-Mediated Decay; Oxidative Stress; Pathology; Pathway interactions; Patients; Phenotype; Preclinical Testing; Proteins; RNA Splicing; Regulation; Resources; Running; Severities; Skeletal Muscle; Stem cells; Tamoxifen; Testis; Therapeutic; Transgenic Mice; WNT Signaling Pathway; Walking; Wheelchairs; base; career; cytotoxicity; design; epigenetic regulation; exhaust; histone modification; male; model development; mouse model; multicatalytic endopeptidase complex; muscle strength; muscular dystrophy mouse model; myogenesis; pathogenic isoform; prevent; protein aggregation; repaired; research clinical testing; targeted treatment; therapeutic development; therapeutic target; tool; transcription factor

PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent myopathy afflicting males and females, children and adults. In the majority of clinical FSHD cases, muscle weakness is not noticeable until the second or third decade of life followed by a progressive pathology impacting many facets of everyday life, ranging from being unable to comb ones own hair or walk the dog to including having to change or abandon careers, loss of independence and, in ~20% of FSHD patients, becoming wheelchair bound an/or require aid in breathing. Currently there are no treatments to slow down, stop, or reverse disease progression. A major impediment to developing ameliorative treatments is the lack of a reliable phenotypic FSHD-like animal model based on expression of the DUX4 gene, widely considered the key mediator of FSHD pathophysiology. This project directly addresses this void. In FSHD, increased expression of DUX4-fl, which can function as a DNA-binding transcription factor, alters the gene expression profiles of muscles and initiates a cascade of events ultimately leading to FSHD pathophysiology. Thus, the DUX4-fl mRNA, DUX4- FL protein and downstream targets are all excellent targets for therapeutic development. For this project, we have successfully engineered a line of transgenic mice that contains the human DUX4- fl gene maintaining its native gene structure. These mice are validated to express correctly spliced DUX4-fl mRNA upon Cre-mediated recombination and develop an aberrant muscle phenotype when DUX4-fl is expressed in developing muscle. This data strongly supports the ultimate generation of an FSHD-like model mouse; however, the precise expression conditions that will result in a useful FSHD-like phenotype are still not known. Here, we will use a commercially available line of mice expressing tamoxifen-inducible Cre in skeletal muscles to determine the conditions required to generate reproducible FSHD-like phenotypes over a range of severities. A successful FSHD-like mouse will appear initially healthy, then develop a progressive myopathic phenotype based on quantifiable metrics of muscle strength and function including grip strength, rotarod, and the maximum distance each is capable of running before becoming exhausted. The phenotypes will be confirmed by FSHD-like gene expression analysis and histopathology. Completion of this project will provide the FSHD field with valuable tools for better understanding FSHD pathogenic progression and mechanisms. In addition, these models will serve as a resource for pre-clinical testing of therapeutic strategies targeting the DUX4-fl mRNA and protein as ameliorative treatments for FSHD.

项目总结