Pathogenic Mechanisms in Facioscapulohumeral Muscular Dystrophy

面肩肱型肌营养不良症的发病机制

• 批准号: 9277391
• 负责人: Peter L Jones
• 金额: $ 53.37万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277391
• 关键词: 4q35; Address; Adult; Adverse effects; Affect; Animal Model; Biological Markers; Biopsy; Breathing; Canis familiaris; Cell Survival; Cell physiology; Cells; Characteristics; Child; Chromosomes; Clinical; Clinical Trials; Comb animal structure; D4Z4; Data; Development; Disease; Disease Pathway; Disease Progression; Enhancers; Epigenetic Process; Event; Facioscapulohumeral Muscular Dystrophy; Female; Functional disorder; Gene Conversion; Gene Expression; Gene Expression Profile; Generations; Genes; Genomics; Goals; Hair; Histology; Human; Immune; Immune response; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory Response; Innate Immune Response; Knowledge; Lead; Life; Mediating; Messenger RNA; Modeling; Molecular Target; Mus; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Myoblasts; Myopathy; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Persons; Phenotype; Physical Performance; Physiology; Play; Population; Primates; RNA Splicing; Reporter; Repression; Resources; Role; Severities; Skeletal Muscle; Somatic Cell; Stratification; Surrogate Markers; Testis; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Organisms; Validation; Variant; Walking; Wheelchairs; Xenograft procedure; base; career; human fetus tissue; in vivo; insight; male; mature animal; model design; mouse model; nonhuman primate; novel; novel therapeutics; offspring; pathogenic isoform; potential biomarker; promoter; spatiotemporal; therapeutic target; 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 one's 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 and/or require aid in breathing. Currently there are no treatments to slow down, stop, or reverse disease progression. Recent advances have identified the aberrant expression of the DUX4 transcription factor as the primary initiator of the FSHD pathogenic cascade of events. In vitro studies have identified numerous DUX4-mediated events that have adverse effects on cell viability and function and could conceivably lead to muscle disease if they were to happen in the context of an actual person. However, due to the complexities of FSHD and the lack of any valid animal model for FSHD, which, if any, of these pathways actually has pathogenic relevance. We have successfully generated and validated a phenotypic FSHD-like mouse model based on DUX4 expression. This allows, for the first time, the interrogation of downstream effects of DUX4 expression as to potential roles in pathophysiology and validation as therapeutic targets. We will initially focus on the innate immune response. The major gene expression signature from FSHD muscle biopsies indicates the immune response is highly activated in FSHD muscle. Many other muscular dystrophies have immune system components and there are many available ameliorative treatments for these muscular dystrophies that target the inflammatory response. Identifying the inflammatory response as a key mechanism in developing FSHD pathology would be a significant advance and open many new avenues for therapeutic intervention. In addition, the design of the model allows us to initiate DUX4 expression in adult animals. Therefore, we will use our FSHD-like mouse model to identify potential biomarkers of disease progression and compare with what has been found in human biospecimens. Importantly, in our mice we will be able to distinguish early, initiating events from those due to long-term cumulative effects and this may help determine which biomarkers correlate more directly with DUX4 expression and are the best to follow as the field moves to clinical trials.

项目概要 面肩肱型肌营养不良症 (FSHD) 是男性和女性中最常见的肌病 女性、儿童和成人。在大多数临床 FSHD 病例中，肌肉无力并不明显 直到生命的第二个或第三个十年，随后出现影响许多方面的进行性病理学 日常生活中，从无法自己梳头或遛狗到不得不 改变或放弃职业、失去独立性，并且约 20% 的 FSHD 患者变得 坐轮椅和/或需要呼吸辅助。目前没有任何治疗方法可以减缓 降低、停止或逆转疾病进展。最近的进展发现了异常表达 DUX4 转录因子作为 FSHD 致病级联事件的主要引发剂。在 体外研究已发现许多 DUX4 介导的事件对细胞产生不利影响 活力和功能，如果发生在肌肉中，可能会导致肌肉疾病 真实人物的背景。然而，由于 FSHD 的复杂性和缺乏有效的 FSHD 动物模型，这些途径（如果有的话）实际上具有致病相关性。我们有 成功生成并验证了基于 DUX4 表达的表型 FSHD 样小鼠模型。 这首次允许询问 DUX4 表达的下游效应 在病理生理学和作为治疗靶标的验证中的潜在作用。我们首先将重点关注 先天免疫反应。 FSHD 肌肉活检的主要基因表达特征表明 FSHD 肌肉中的免疫反应高度激活。许多其他的肌肉 营养不良症具有免疫系统成分，并且有许多可用的改善方法 针对炎症反应的肌营养不良症的治疗。识别 炎症反应作为 FSHD 病理学发展的关键机制将具有重要意义 推进并开辟许多治疗干预的新途径。另外，模型的设计 使我们能够在成年动物中启动 DUX4 表达。因此，我们将使用类似 FSHD 的 小鼠模型来识别疾病进展的潜在生物标志物并与 已在人类生物样本中发现。重要的是，在我们的小鼠中，我们将能够区分 早期，由于长期累积效应而引发的事件，这可能有助于确定 哪些生物标志物与 DUX4 表达更直接相关，并且是该领域最好遵循的 转向临床试验。