Regulation of Myoblast Fusion

描述（由申请人提供）：成肌细胞融合对于肌管/肌纤维形成、生长和维持至关重要。我们以前的工作已经确定，哺乳动物的肌管形成发生在两个阶段的过程。最初，成肌细胞彼此融合形成小的新生肌管。新生肌管的亚群分泌细胞因子IL-4，导致额外成肌细胞的募集和融合以及大的成熟肌管的形成。关于成肌细胞融合第二阶段的分子调控机制知之甚少。在几种细胞类型中，IL-4调节甘露糖受体（MR）的表达，MR是一种在许多细胞类型表面表达的C型凝集素。几个角色已被归因于MR。重要的是，对于这个提议，MR在细胞粘附和识别中起作用，并与巨噬细胞融合有关。我们的初步数据确定MR作为成肌细胞融合的第二阶段的一种新的调节剂，并建议MR的功能下游的IL-4信号。本研究的总体目标是了解MR如何调节成肌细胞融合的第二阶段。为此，我们将在体外和体内分析MR无效小鼠肌发生的各个方面。提出了一组4个具体目标，以分析MR功能和体外作用机制（目标1），分析MR功能在肌肉再生过程中的体内（目标2），确定MR是否与已知的调节融合的途径（目标3）和识别其配体（目标4）。我们提出的研究将确定一个新的途径在骨骼肌调节成肌细胞融合。对MR的研究可能会导致在疾病、修复和衰老中操纵成肌细胞的新策略，并确定增强肌肉生长的新治疗靶点。

DESCRIPTION (provided by applicant): Myoblast fusion is critical for myotube/myofiber formation, growth and maintenance. Our previous work has defined that myotube formation in mammals occurs in a two-stage process. Initially, myoblasts fuse with one another to form small nascent myotubes. A subset of nascent myotubes secretes the cytokine IL-4 leading to the recruitment and fusion of additional myoblasts and the formation of large mature myotubes. Little is known about the molecular mechanisms regulating this second phase of myoblast fusion. In several cell types IL-4 regulates expression of the mannose receptor (MR), a C-type lectin expressed on the surface of a number of cell types. Several roles have been ascribed to the MR. Importantly for this proposal the MR plays a role in cell adhesion and recognition and is implicated in macrophage fusion. Our preliminary data identify the MR as a novel regulator of the second phase of myoblast fusion and suggest that the MR functions downstream of IL-4 signaling. The overall goal of this proposal is to understand how the MR regulates the second phase of myoblast fusion. Towards this end we will analyze various aspects of myogenesis in MR null mice in vitro and in vivo. A set of 4 specific aims are proposed to analyze MR function and mechanism of action in vitro (Aim 1), analyze MR function during muscle regeneration in vivo (Aim 2), determine if the MR is associated with known pathways that regulate fusion (Aim 3) and identify its ligand (Aim 4). Our proposed studies will define a novel pathway in skeletal muscle for regulating myoblast fusion. Studies of the MR may lead to new strategies for manipulating myoblasts in disease, repair and aging and define novel therapeutic targets for enhancing muscle growth.