Mechanisms of Nup210 Regulation of Muscle Development and Regeneration

描述（由申请人提供）：核孔复合物（NPCs）是穿透核膜并连接细胞核和细胞质的多蛋白通道。除了控制核细胞质运输外，NPCs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与成肌细胞分化有关，表明特殊的npc在肌肉生理学中的作用。在成人中，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。由于卫星细胞对肌肉修复和再生至关重要，因此这些细胞的移植对于治疗受损肌肉、肌肉萎缩症和肌肉减少症是一种很有前景的治疗方法。因此，了解卫星细胞的功能机制已成为再生医学研究的热点。先前的研究发现，核孔复合物蛋白Nup210的表达是成肌细胞分化和存活所必需的，表明该蛋白在骨骼肌分化和再生中起着至关重要的作用。此外，在成肌细胞中上调Nup210水平已被证明可以加速肌肉生成，这表明调节其活性可以用来刺激肌肉再生。本提案的总体目标是建立核孔蛋白Nup210调节肌肉形成的分子机制，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，我们希望确定Nup210在肌肉形成、生长和修复中的作用（目的1），并确定Nup210调节肌肉生成的分子机制（目的2）。此外，我们将确定调节这种核孔复合物组分的活性是否可以刺激肌肉再生并逆转营养不良的成肌细胞的肌原性缺陷。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直接刺激肌肉愈合和预防肌肉变性的治疗方法的关键步骤。我们在这里的贡献有望是详细了解Nup210在肌肉发生、肌肉发育和肌肉再生中的作用。这些研究将大大提高我们对核孔复合物组成和功能的变化如何调节这些过程的认识，并可能发现新的靶点，从而开发出改善肌肉功能或预防肌肉变性的疗法。

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.