Model Studies for FSHD Biomarkers

FSHD 生物标志物的模型研究

• 批准号: 7917473
• 负责人: Jeffrey Boone Miller
• 金额: $ 27.2万
• 依托单位: BOSTON BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7917473
• 关键词: Affect; Apoptosis; Apoptotic; Atrophic; Biological Markers; Cell Death; Cells; Child; Clinical Trials; Crystallins; Disease; Disease Progression; Disease model; Facioscapulohumeral Muscular Dystrophy; Failure; Fiber; G22P1 gene; Growth; Human; Hypertrophy; IGF1 gene; Knowledge; Laboratories; Lead; Maryland; Massachusetts; Methods; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Mutation; Myoblasts; Myopathy; Natural regeneration; Necrosis; Neuromuscular Diseases; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Predisposition; Production; Proteomics; Public Health; Research Design; Research Personnel; Resources; Role; Route; Study models; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Universities; Work; caspase-3; design; gene therapy; improved; inhibitor/antagonist; medical schools; mouse genome; mouse model; muscle hypertrophy; muscular dystrophy mouse model; myostatin; overexpression; repaired; research study

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.

项目4：FSHD生物标志物的模型研究。虽然遗传变化是facioscapulohumeral的 已经鉴定出肌肉营养不良（FSHD），需要识别下游的致病 机制并找到其他疾病生物标志物。因此，项目4下的研究将集中 关于使用潜在的小鼠模型和培养的人FSHD肌肉细胞来发现或验证 FSHD生物标志物，（ii）鉴定下游的致病机制和（iii）测试可能的疗法。 由于受影响的FSHD肌肉仅显示少量再生和修复，因此有可能 如果增加再生和/或肌肉肥大，可以改善FSHD病理学。一组 因此，实验将确定这种治疗是否会减少潜在的疾病生物标志物 FSHD鼠标模型。此外，还有大量间接证据支持凋亡的想法 有助于FSHD发病机理，例如，在人FSHD肌肉纤维中发现了激活的caspase-3，并且 人FSHD肌原细胞似乎更容易受到细胞死亡的影响。尚未直接研究 评估了凋亡对FSHD发病机理的贡献和肌肉细胞的机制 凋亡尚不完全了解。其他研究旨在提供直接的研究 评估凋亡在FSHD中的作用，调查凋亡作为疾病生物标志物的迹象和 阐明患病肌肉细胞中的凋亡途径。 项目4的具体目的是：（1）在FSHD小鼠模型中确定凋亡是否有助于 发病机理和凋亡的迹象是有效的疾病生物标志物； （2）确定是否治疗 改善再生和/或诱导肥大将减少FSHD模型中的疾病生物标志物；和 （3）阐明人类FSHD成肌细胞和肌管的易感性增加的基础 在氧化应激时进行细胞死亡。 与公共卫生有关。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。实验也可以识别 可以改善FSHD的新方法。