Molecular Mechanisms of Neuronal-dependent Muscle Plasticity

神经元依赖性肌肉可塑性的分子机制

基本信息

批准号：
8432447
负责人：
Graciela Alexandra Unguez
金额：
$ 27.41万
依托单位：
NEW MEXICO STATE UNIVERSITY LAS CRUCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432447
关键词：
Address Adult Affect Aging Binding Biochemical Biological Assay Biological Models Biology Calcineurin Cells Code Collection Coupled Data Degenerative Disorder Down-Regulation Electric Fish Electric Organ Ensure Failure Fishes Frequencies Gene Expression Gene Targeting Genes Goals Health Hereditary Disease Human Investigation Knowledge Lead Life Link Maintenance Mammals Mediating Mentorship Modern Medicine Modification Molecular Motor Neurons Muscle Muscle Cells Muscle Development Muscle Fibers Muscle Proteins Muscle function Myogenic Regulatory Factors Myopathy Nerve Nervous system structure Neurons Organism Patients Pattern Performance Phenotype Play Process Property Proteins Regulation Regulator Genes Research Role Signal Pathway Skeletal Muscle Skeletal muscle injury System Testing Therapeutic Time Tissues Transcript Transcriptional Activation Transcriptional Regulation Translating Trauma Vertebrates chromatin immunoprecipitation in vivo innovation meetings neuromuscular neuroregulation programs public health relevance relating to nervous system repaired skills therapeutic development therapy development tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Two current challenges in the repair of skeletal muscle injury or failure due to degenerative disease, genetic conditions, aging, or trauma are: 1) advancing our understanding of how the mature muscle cell phenotype is maintained, and 2) identification and modification of nerve-dependent processes that are coupled to changes in muscle properties. Meeting these challenges will have critical implications for development of therapies directed toward patients with impaired muscle function. The electric fish Sternopygus macrurus is a powerful vertebrate model system that can help elucidate cellular and molecular mechanisms that affect different features of the muscle program. In S. macrurus, some skeletal muscle fibers fully differentiate only to undergo fusion and subsequent extreme modifications in their morphological and biochemical properties to convert into non-contractile electrogenic cells called electrocytes. Mature electrocytes retain a partial muscle phenotype by continuing to express some, but not all muscle-specific proteins. The suppression of select muscle gene expression in electrocytes is dependent on a continuous, high frequency electrical activation pattern. Further, this deficient muscle phenotype in electrocytes is reversible upon changes in nerve activity patterns. Preliminary data intensified our goal to identify the molecular processes involved in mediating the activity-dependent remodeling of the skeletal muscle program. Specifically, we will test the hypothesis that the transcriptional mechanisms that mediate neural activity-dependent regulation of muscle genes in skeletal muscle differ in electrocytes of S. macrurus. The specific aims of this proposal are: 1) to determine the transcript profiles in skeletal muscle and electrocytes; 2) to characterize the role of the calcineurin/NFAT signaling pathway in mediating the neural-dependent regulation of the muscle program in electrocytes, and 3) to identify the genes regulated by myogenic transcription factors in muscle cells versus electrocytes. To ensure the successful completion of the studies proposed, we have established the amenability of S. macrurus to in vivo experimentation using a collection of molecular and cellular tools, and assembled a research team with strong mentorship support and complementary skills and knowledge in neuromuscular biology. This research is expected to enhance our understanding of the processes by which neural input controls myogenic gene expression and maintenance of the muscle phenotype - an understanding of muscle function with critical implications to therapeutic approaches for human muscle diseases.

描述（由申请人提供）：当前修复因退行性疾病、遗传条件、衰老或创伤导致的骨骼肌损伤或衰竭的两个挑战是：1）加深我们对如何维持成熟肌肉细胞表型的理解，2 ）识别和修改与肌肉特性变化相关的神经依赖性过程。应对这些挑战将对针对肌肉功能受损患者的疗法的开发产生重大影响。电鱼 Sternopygus macrurus 是一个强大的脊椎动物模型系统，可以帮助阐明影响肌肉程序不同特征的细胞和分子机制。在 S. macrurus 中，一些骨骼肌纤维完全分化，仅经历融合和随后其形态和生化特性的极端改变，转化为称为电细胞的非收缩性发电细胞。成熟的电细胞通过继续表达一些但不是全部肌肉特异性蛋白质来保留部分肌肉表型。电细胞中特定肌肉基因表达的抑制依赖于连续的高频电激活模式。此外，电细胞中这种缺陷的肌肉表型在神经活动模式的变化时是可逆的。初步数据强化了我们的目标，即确定参与介导骨骼肌程序的活动依赖性重塑的分子过程。具体来说，我们将测试以下假设：介导骨骼肌中肌肉基因的神经活动依赖性调节的转录机制在 S. macrurus 的电细胞中有所不同。该提案的具体目标是：1）确定骨骼肌和电细胞的转录谱； 2) 表征钙调神经磷酸酶/NFAT 信号通路在介导电细胞中肌肉程序的神经依赖性调节中的作用，以及 3) 鉴定肌肉细胞与电细胞中受肌源性转录因子调节的基因。为了确保成功完成拟议的研究，我们使用一系列分子和细胞工具建立了 S. macrurus 的体内实验能力，并组建了一个研究团队，该团队在神经肌肉生物学方面拥有强大的指导支持和互补的技能和知识。这项研究预计将增强我们对神经输入控制生肌基因表达和肌肉表型维持过程的理解——对肌肉功能的理解对人类肌肉疾病的治疗方法具有重要意义。