Mechanisms of Nup210 Regulation of Muscle Development and Regeneration

Nup210 调节肌肉发育和再生的机制

• 批准号: 9463290
• 负责人: Maximiliano A DAngelo
• 金额: $ 13.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9463290
• 关键词: Adult; Aging; Animals; Biological Assay; Cell Nucleus; Cell Transplantation; Cell physiology; Cells; Chromatin; Cytoplasm; Defect; Development; Differentiated Gene; Down-Regulation; Embryo; Facioscapulohumeral; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; In Vitro; Injury; Knowledge; LIM Domain Protein; Lamin Type A; Lead; Link; Maintenance; Molecular; Molecular Mechanisms of Action; Multiprotein Complexes; Muscle; Muscle Development; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Mutation; Myoblasts; Myopathy; Myotonic Dystrophy; Natural regeneration; Nuclear Envelope; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Oculopharyngeal Muscular Dystrophy; Outcome; Pathway interactions; Phenotype; Physiology; Play; Process; Proliferating; Proteins; Regenerative Medicine; Regulation; Regulator Genes; Role; Skeletal Muscle; Structure; System; Therapeutic; Up-Regulation; Work; Zebrafish; base; design; emerin; genetic approach; healing; improved; in vivo; interest; muscle degeneration; muscle form; muscle physiology; muscle regeneration; muscular structure; myogenesis; novel; novel therapeutics; nucleocytoplasmic transport; overexpression; prevent; public health relevance; repaired; sarcopenia; satellite cell; skeletal muscle differentiation; skeletal muscle wasting; therapeutic target; therapy development; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Nuclear pore complexes (NPCs) are multiprotein channels that penetrate the nuclear envelope and connect the nucleus with the cytoplasm. Besides controlling nucleocytoplasmic transport, NPCs are involved in chromatin organization and gene expression regulation. Changes in the composition of these structures have been recently linked to myoblast differentiation, suggesting a role for specialized NPCs in muscle physiology. In adults, muscle regeneration and repair requires the efficient function of satellite cells. Upon injury, these muscle stem cells are induced to proliferate, differentiate into myoblasts and fuse to regenerate muscle fibers. Because satellite cells are essential for muscle repair and regeneration, transplantation of these cells represents a promising therapy for the treatment of damaged muscle, muscular dystrophies and sarcopenia. Therefore, understanding the mechanisms of satellite cell function has become of great interest for regenerative medicine. Previous studies have found that the expression of the nuclear pore complex protein Nup210 is required for myoblast differentiation and survival, indicating an essential role for this protein i skeletal muscle differentiation and regeneration. Additionally, up-regulation of Nup210 levels in myoblasts has been shown to accelerate myogenesis, suggesting that modulation of its activity could be exploited to stimulate muscle regeneration. The overall objectives of this proposal are to establish the molecular mechanisms through which the nucleoporin Nup210 regulates myogenesis and to define its function in muscle formation and maintenance, with the ultimate goal of defining its potential as a therapeutic target for muscle regeneration. By combining in vivo and in vitro genetic approaches with muscle injury studies we expect to establish the role of Nup210 in muscle formation, growth and repair (Aim 1) and define the molecular mechanisms of myogenic regulation by Nup210 (Aim 2). In addition, we will determine if modulating the activity of this nuclear pore complex component can stimulate muscle regeneration and reverse the myogenic defects of dystrophic myoblasts. Defining the function of Nup210 in muscle physiology and understanding its molecular mechanisms of action are critical steps to determine whether this pathway could be used to develop therapies directed to stimulate muscle healing and prevent muscle degeneration. Our contribution here is expected to be a detailed understanding of the role of Nup210 in myogenesis, muscle development and muscle regeneration. These studies will significantly advance our knowledge of how changes in nuclear pore complex composition and function regulate these processes and could uncover new targets on which therapies to improve muscle function or prevent muscle degeneration can be developed.

描述（由申请人提供）：核孔复合物（NPC）是穿透核膜并连接细胞核与细胞质的多蛋白通道。除了控制核质转运外，NPC还参与染色质组织和基因表达调控。这些结构组成的变化最近已与成肌细胞分化有关，这表明了专门的NPC在肌肉生理学中的作用。在成年人中，肌肉再生和修复需要卫星细胞的有效功能。损伤后，这些肌肉干细胞被诱导增殖，分化成成肌细胞并融合再生肌纤维。由于卫星细胞对于肌肉修复和再生是必不可少的，因此这些细胞的移植代表了用于治疗受损肌肉、肌营养不良症和少肌症的有前景的疗法。因此，了解卫星细胞功能的机制已成为再生医学的极大兴趣。先前的研究发现，核孔复合体蛋白Nup 210的表达是成肌细胞分化和生存所需的，表明该蛋白在骨骼肌分化和再生中发挥着重要作用。此外，成肌细胞中Nup210水平的上调已被证明可加速肌生成，这表明其活性的调节可用于刺激肌肉再生。该提案的总体目标是建立核孔蛋白Nup210调节肌肉发生的分子机制，并确定其在肌肉形成和维持中的功能，最终目标是确定其作为肌肉再生治疗靶点的潜力。通过将体内和体外遗传学方法与肌肉损伤研究相结合，我们期望建立Nup210在肌肉形成、生长和修复中的作用（Aim 1），并定义Nup210的成肌调节的分子机制（Aim 2）。此外，我们将确定是否调节这种核孔复合物组分的活性可以刺激肌肉再生和逆转营养不良成肌细胞的肌源性缺陷。确定Nup210在肌肉生理学中的功能并了解其分子作用机制是确定该途径是否可用于开发刺激肌肉愈合和预防肌肉退化的疗法的关键步骤。我们在这里的贡献预计是详细了解Nup210在肌肉发生，肌肉发育和肌肉再生中的作用。这些研究将大大推进我们对核孔复合物组成和功能变化如何调节这些过程的认识，并可能发现新的靶点，从而开发改善肌肉功能或预防肌肉退化的疗法。