Pathogenic Mechanisms in Facioscapulohumeral Muscular Dystrophy

项目摘要 面肩肱型肌营养不良症（FSHD）是困扰男性的最普遍的肌病， 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，随后是影响许多方面的进行性病理学， 日常生活中，从不能自己梳头或遛狗到不得不 改变或放弃职业，失去独立性，约20%的FSHD患者， 轮椅束缚和/或需要呼吸辅助。目前还没有治疗方法来减缓 阻止或逆转疾病进展。最近的研究发现， DUX 4转录因子作为FSHD致病性级联事件的主要启动子。在 体外研究已经确定了许多DUX 4介导的事件， 生存能力和功能，并可能导致肌肉疾病，如果他们发生在 一个真实的人。然而，由于FSHD的复杂性和缺乏任何有效的 FSHD的动物模型，如果有的话，这些途径实际上具有致病相关性。我们有 成功地产生并验证了基于DUX 4表达的表型FSHD样小鼠模型。 这首次允许询问DUX 4表达的下游效应， 在病理生理学中的潜在作用和作为治疗靶点的验证。我们将首先关注 先天免疫反应FSHD肌肉活检的主要基因表达特征表明， 免疫应答在FSHD肌肉中被高度激活。许多其他肌肉 营养不良具有免疫系统成分， 针对炎症反应的肌营养不良症的治疗方法。识别 炎症反应作为发展FSHD病理学的关键机制将是重要的 推进并开辟了许多新的治疗干预途径。此外，模型的设计 使我们能够在成年动物中启动DUX 4的表达。因此，我们将使用类似FSHD的 小鼠模型，以确定疾病进展的潜在生物标志物， 在人类生物标本中发现重要的是，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DUX 4表达更直接相关，并且是最好的领域 进行临床试验

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.