Smad Signaling in Skeletal Muscle as a Biomarker of Disease Progression in ALS

骨骼肌中的 Smad 信号转导作为 ALS 疾病进展的生物标志物

基本信息

批准号：
9222815
负责人：
PETER H KING
金额：
$ 32.16万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222815
关键词：
Address Amyotrophic Lateral Sclerosis Basic Science Biological Markers Biopsy Biopsy Specimen Biosensor Blood Blood specimen Cell Nucleus Cessation of life Clinical Clinical Research Clinical Sciences Clinical Trials Consensus Data Degenerative Disorder Denervation Detection Diagnosis Disease Disease Progression Early Diagnosis Educational workshop Family Funding Gene Expression Genetic Transcription Goals Grant Human Knock-in Lead Ligands Link Measures Mediating MicroRNAs Modeling Molecular Molecular Profiling Monitor Motor Neuron Disease Mus Muscle Muscle Cells Muscle Weakness Nerve Neurodegenerative Disorders Pathologic Patients Pattern Peripheral nerve injury Pharmaceutical Preparations Physiological Play Prospective Studies Proteins Publishing Regulation Reporter Research Personnel Role Sampling Savings Signal Transduction Skeletal Muscle Specificity Specimen Time Transcriptional Regulation Transforming Growth Factor beta Treatment Effectiveness Up-Regulation Validation Work bench to bedside cohort disease diagnosis disorder control improved insight lens member motor neuron degeneration mouse model novel novel therapeutics pre-clinical pri-miRNA prospective public health relevance receptor reinnervation response screening specific biomarkers superoxide dismutase 1 tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): 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, thus often delaying the diagnosis for more than a year. Furthermore, once a diagnosis is established, 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. A workshop of ALS researchers came to a consensus that biomarkers are critically and urgently needed for this disease, especially those that can track disease progression. In an exploratory R21 grant, using an RNA sequencing approach, we identified members of the Smad family as promising muscle biomarkers of ALS (Si et al., 2014). Smads mediate TGFβ and BMP signal transduction by modulating gene transcription and miRNA maturation. We found these markers to be significantly elevated in ALS muscle samples, and they tracked disease progression in the G93A mouse model starting at very early (preclinical) stages. From our preliminary RNA sequencing and validation data, we have found: 1) early upregulation of specific TGF ligands that activate Smads and parallel disease progression, and 2) upregulation of specific miRNAs that are targets of Smad modulation. These novel findings form the basis of our overarching hypothesis in this proposal that the Smad axis of signaling in muscle is a biomarker of ALS. The long term goal is to develop this axis as a biomarker of ALS to track the disease and to provide insight into disease mechanisms at the level of muscle. We propose 3 specific aims to address this hypothesis: 1) Characterize the TGF ligands involved in the Smad axis of signaling in ALS muscle using human and mouse ALS muscle tissues and cultured muscle cells. 2) Correlate miRNA expression patterns in human and mouse ALS muscle samples (as determined by miRNA sequencing) to disease progression. We will assess the impact of Smad induction/activation on these patterns. 3) Characterize the Smad axis of signaling as a biosensor of ALS disease progression. In this aim we will prospectively study the Smad axis of signaling in muscle from a cohort of ALS patients and correlate the molecular patterns of Smad induction/activation and miRNA expression with disease progression. This bench-to-bedside proposal represents an entirely novel direction with compelling translational implications. It vertically integrates basic and clinical approaches, capitalizing on the collaborative spirit at UAB, to address a major gap in our ability to manage patients with ALS.

描述（由申请人提供）：肌萎缩性脊髓侧索硬化症（ALS）是一种运动神经元退行性疾病，会不可避免地导致进行性无力和死亡。这种疾病没有特定的生物标志物，因此通常会延迟一年以上的诊断。一旦诊断确定，目前追踪患者的工具对于及时检测疾病改善或恶化并不敏感，能够促进诊断、跟踪疾病进展或两者兼而有之的生物标志物将填补 ALS 的巨大临床空白。 ALS 研究人员的研讨会达成共识，认为这种疾病迫切需要生物标志物，特别是那些可以使用 RNA 测序方法追踪疾病进展的生物标志物。我们发现 Smad 家族的成员是有前途的 ALS 肌肉生物标志物（Si 等，2014）。我们发现了这些标志物通过调节基因转录和 miRNA 成熟来介导 TGFβ 和 BMP 信号转导。在 ALS 肌肉样本中显着升高，并且他们从非常早期（临床前）阶段开始跟踪 G93A 小鼠模型中的疾病进展，从我们的初步 RNA 测序和验证数据中，我们发现：1）特定 TGF 配体的早期上调。激活 Smad 并平行疾病进展，2) 作为 Smad 调节目标的特定 miRNA 的上调。这些新发现构成了我们这一提议的总体假设的基础，即肌肉中的 Smad 信号传导轴是 Smad 的生物标志物。 ALS。长期目标是开发该轴作为 ALS 的生物标志物，以跟踪疾病并深入了解肌肉水平的疾病机制。我们提出了 3 个具体目标来解决这一假设：1）表征所涉及的 TGF 配体。使用人和小鼠 ALS 肌肉组织和培养的肌肉细胞在 ALS 肌肉的 Smad 信号轴中进行研究。 2) 将人和小鼠 ALS 肌肉样本中的 miRNA 表达模式（通过 miRNA 测序确定）与疾病进展相关联。的3) 将 Smad 信号轴表征为 ALS 疾病进展的生物传感器。为此，我们将前瞻性研究一组 ALS 患者肌肉中的 Smad 信号轴，并将其分子模式关联起来。 Smad 诱导/激活和 miRNA 表达与疾病进展的关系代表了一个全新的方向，具有引人注目的转化意义，它垂直整合了基础知识。和临床方法，利用 UAB 的协作精神，解决我们管理 ALS 患者能力方面的重大差距。