Model Studies for FSHD Biomarkers

项目4：FSHD生物标志物的模型研究。虽然面肩肱关节的遗传变化 肌营养不良症（FSHD）已经确定，有必要确定下游致病 机制，并找到其他疾病的生物标志物。因此，项目4下的研究将侧重于 使用潜在的小鼠模型和培养的人FSHD肌肉细胞来（i）发现或验证 FSHD生物标志物，（ii）确定下游发病机制，（iii）测试可能的治疗方法。 因为受影响的FSHD肌肉只显示少量的再生和修复，所以有可能 FSHD病理可以改善，如果再生和/或肌肉肥大增加。一组 因此，大量的实验将确定这种治疗是否会降低疾病的生物标志物， FSHD小鼠模型。此外，有相当多的间接证据支持细胞凋亡 有助于FSHD发病机制，例如，在人FSHD肌纤维中发现活化的半胱天冬酶-3， 人FSHD肌原性细胞似乎对细胞死亡更敏感。目前还没有研究直接 评估细胞凋亡在FSHD发病机制中的作用，以及肌细胞凋亡的机制。 细胞凋亡尚未完全了解。这些额外的研究旨在提供一个直接的 评估细胞凋亡在FSHD中的作用，研究细胞凋亡作为疾病生物标志物的迹象， 阐明患病肌肉细胞的凋亡途径。 项目4的具体目标是：（1）确定FSHD小鼠模型中细胞凋亡是否有助于 发病机制和细胞凋亡的迹象是否是有效的疾病生物标志物;（2）确定 改善再生和/或诱导肥大将减少FSHD模型中疾病生物标志物;和 (3)阐明人FSHD成肌细胞和肌管易感性增加的机制 氧化应激导致细胞死亡 与公共卫生相关。这些研究将增加我们对疾病生物标志物的了解 进展以及遗传变化如何导致FSHD疾病。这些实验还可以识别 改善FSHD的可能新方法。

Project 4: Model Studies for FSHD Biomarkers. Though genetic changes underlying facioscapulohumeral muscular dystrophy (FSHD) have been identified, there is a need to identify downstream pathogenetic mechanisms and to find additional disease biomarkers. Accordingly, the studies under Project 4 will focus on the use of potential mouse models and cultured human FSHD muscle cells to (i) discover or validate FSHD biomarkers, (ii) identify downstream pathogenetic mechanisms, and (iii) test possible therapies. Because affected FSHD muscles show only a small amount of regeneration and repair, it is possible that FSHD pathology could be ameliorated if regeneration and/or muscle hypertrophy were increased. One set of experiments, therefore, will determine if such treatments decrease biomarkers of disease in potential FSHD mouse models. Also, there is considerable indirect evidence to support the idea that apoptosis contributes to FSHD pathogenesis, e.g., activated caspase-3 is found in human FSHD muscle fibers and human FSHD myogenic cells appear to be more susceptible to cell death. No studies have yet directly assessed the contribution of apoptosis to FSHD pathogenesis, and the mechanisms of muscle cell apoptosis are not fully understood. The additional sets of studies are designed to provide a direct assessment of the role of apoptosis in FSHD, to investigate signs of apoptosis as disease biomarkers, and to elucidate apoptotic pathways in diseased muscle cells. The Specific Aims of Project 4 are to: (1) Determine in FSHD mouse models if apoptosis contributes to pathogenesis and if signs of apoptosis are valid disease biomarkers; (2) Determine if treatments that improve regeneration and/or induce hypertrophy will decrease disease biomarkers in FSHD models; and (3) Elucidate mechanisms underlying the increased susceptibility of human FSHD myoblasts and myotubes to cell death upon oxidative stress. Relevance to Public Health. The studies will increase our knowledge of biomarkers for disease progression and how genetic changes lead to disease in FSHD. The experiments could also identify possible new methods to ameliorate FSHD.