Regulation of Myoblast Fusion

描述（由申请人提供）：成肌细胞融合对肌管/肌纤维的形成、生长和维持至关重要。我们以前的工作已经确定，哺乳动物肌管的形成发生在两个阶段的过程。最初，成肌细胞相互融合形成小的新生肌管。新生肌管的一个子集分泌细胞因子IL-4，导致额外的成肌细胞募集和融合，形成大的成熟肌管。调控成肌细胞融合第二阶段的分子机制尚不清楚。在几种细胞类型中，IL-4调节甘露糖受体（MR）的表达，甘露糖受体是一种在许多细胞类型表面表达的c型凝集素。MR具有多种作用，重要的是MR在细胞粘附和识别中起作用，并与巨噬细胞融合有关。我们的初步数据表明，MR是成肌细胞融合第二阶段的一种新型调节剂，并表明MR在IL-4信号传导的下游发挥作用。本提案的总体目标是了解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无MR小鼠肌肉发生的各个方面。提出了一组4个特定目标来分析MR在体外的功能和作用机制（Aim 1），分析MR在体内肌肉再生中的功能（Aim 2），确定MR是否与调节融合的已知途径相关（Aim 3），并确定其配体（Aim 4）。我们提出的研究将在骨骼肌中定义一条调节成肌细胞融合的新途径。磁共振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，并确定促进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.