Molecular Signatures of Amyotrophic Lateral Sclerosis in Skeletal Muscle

骨骼肌肌萎缩侧索硬化症的分子特征

• 批准号: 8619114
• 负责人: PETER H KING
• 金额: $ 22.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619114
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Archives; Atrophic; Biological Markers; Biopsy Specimen; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Consensus; Data; Degenerative Disorder; Detection; Diagnosis; Disease; Disease Management; Disease Progression; Early Diagnosis; Educational workshop; Enrollment; Fiber; Funding; Gene Expression Profile; Goals; Histology; Intervention; Laboratories; Messenger RNA; Molecular; Molecular Profiling; Molecular Target; Monitor; Motor Neurons; Mus; Muscle; Muscle Weakness; Neurodegenerative Disorders; Neuromuscular Diseases; Neuromuscular Junction; Organ; Paralysed; Patients; Pattern; Pharmaceutical Preparations; Phase; Positioning Attribute; Process; Protein Isoforms; Proteins; Research Personnel; Sampling; Sequence Analysis; Skeletal Muscle; Specificity; Staging; Testing; Time; Tissues; Treatment Efficacy; Variant; Work; base; clinical Diagnosis; cohort; deep sequencing; disease diagnosis; disorder control; effective therapy; improved; mitochondrial dysfunction; mouse model; neuromuscular; next generation; novel; novel therapeutics; patient population; pre-clinical; protein expression; public health relevance; tool

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that inexorably leads to progressive weakness and death. There is no specific biomarker for this disease, and the diagnosis is often delayed as clinical and electrophysiological examinations are often inconclusive in the early stages. Furthermore, once a diagnosis is estabished, the current tools to track patients are insensitive for the timely detection of disease improvement or worsening. A biomarker that can facilitate diagnosis, track disease progression, or both, would fill a large clinical gap in ALS management, and expedite clinical trials of novel therapies. The long term goal of this proposal is to identify molecular signatures in muscle of ALS patients that can serve as disease biomarkers. In ALS, changes occur in skeletal muscle prior to motor neuron death and clinical onset, such as structural changes in the neuromuscular junction, muscle restricted mitochondrial dysfunction, and fiber atrophy. Muscle is the "end organ" affected by the degenerative process of ALS and is the most accessible for molecular study. Here we hypothesize that gene expression patterns in muscle from patients with ALS contain molecular signatures that can serve as biomarkers of the disease. This hypothesis is based on preliminary data we obtained using next generation deep sequencing on muscle samples of clinically well characterized ALS patients. Using non-ALS disease- and normal control samples, we identified over 300 unique targets in ALS samples, including isoform variances, that will serve as the basis of study for this proposal. We are well positioned to carry out this study because of the large neuromuscular patient population, including ALS and ALS mimics, and our oversight of the electrodiagnostic and muscle histology laboratories. Here, we will further investigate our molecular targets with the following two specific aims: Specific Aims: 1. To validate ALS-specific targets and isoform variances identified by deep sequencing by performing PCR analysis of a large cohort of ALS and non-ALS muscle samples. 2: To assess protein expression of validated targets in muscle tissues from ALS patients and correlate targets with muscle samples from the G93A SOD1 ALS mouse.

肌萎缩性侧索硬化症（ALS）是一种运动神经元的退行性疾病， 逐渐衰弱和死亡这种疾病没有特异性的生物标志物，诊断通常是 延迟，因为临床和电生理检查在早期阶段往往没有定论。 此外，一旦诊断建立，当前用于跟踪患者的工具对于及时诊断是不敏感的。 检测疾病改善或恶化。一种生物标志物，可以帮助诊断，跟踪疾病 进展，或两者兼而有之，将填补ALS管理中的巨大临床空白，并加快新的药物的临床试验。 治疗该提案的长期目标是鉴定ALS患者肌肉中的分子特征， 可以作为疾病的生物标志物。在ALS中，运动神经元死亡之前骨骼肌发生变化， 临床发作，如神经肌肉接头的结构变化，肌肉限制性线粒体 功能障碍和纤维萎缩。肌肉是受ALS退化过程影响的“终末器官”， 最容易进行分子研究。在这里，我们假设肌肉中的基因表达模式， 患有ALS的患者含有可作为该疾病的生物标志物的分子特征。这种假设是 基于我们使用下一代深度测序对临床上患有癌症的患者的肌肉样品获得的初步数据， 很好地描述了ALS患者。使用非ALS疾病和正常对照样本，我们确定了300多个 ALS样本中的独特目标，包括同种型差异，将作为本研究的基础。 提议由于神经肌肉患者人群庞大，我们有能力开展这项研究， 包括ALS和ALS模拟物，以及我们对电诊断和肌肉组织学实验室的监督。 在这里，我们将进一步研究我们的分子靶标，具体目标如下： 具体目标： 1.通过进行PCR验证通过深度测序鉴定的ALS特异性靶标和亚型差异 ALS和非ALS肌肉样品的大群组的分析。 2：评估来自ALS患者的肌肉组织中验证的靶标的蛋白质表达和相关靶标 用来自G93A SOD1 ALS小鼠的肌肉样品。