Regulation of Myoblast Fusion

成肌细胞融合的调节

• 批准号: 7392314
• 负责人: Grace K Pavlath
• 金额: $ 28.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-12 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392314
• 关键词: Acetylglucosamine; Aging; Atrophic; C-Type Lectins; Cell Adhesion; Cell fusion; Cell surface; Cell-Cell Adhesion; Cells; Data; Disease; Embryonic Development; Family; Fucose; Glycoproteins; Goals; Growth; Hyperplasia; Hypertrophy; Immune; In Vitro; Individual; Injury; Inorganic Sulfates; Integral Membrane Protein; Interleukin-4; Knockout Mice; Lead; Life; Ligands; Localized; Maintenance; Mammals; Mannose; Molecular; Muscle; Muscle Cells; Muscle Fibers; Myoblasts; Natural regeneration; Numbers; Pathway interactions; Phase; Play; Process; Regulation; Research Personnel; Role; Signal Transduction; Skeletal Muscle; Staging; Surface; Unspecified or Sulfate Ion Sulfates; Work; cell type; cellular targeting; cytokine; in vivo; macrophage; mannose receptor; member; muscle regeneration; myogenesis; novel; novel therapeutics; receptor; receptor binding; receptor function; repaired; therapeutic target

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.

描述（由申请人提供）：成肌细胞融合对于肌管/肌纤维的形成、生长和维持至关重要。我们之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中。最初，成肌细胞彼此融合形成小的新生肌管。一部分新生肌管分泌细胞因子 IL-4，导致额外成肌细胞的募集和融合以及大型成熟肌管的形成。关于调节成肌细胞融合第二阶段的分子机制知之甚少。在多种细胞类型中，IL-4 调节甘露糖受体 (MR) 的表达，甘露糖受体是一种在多种细胞类型表面表达的 C 型凝集素。 MR 被赋予了多种角色。对于该提议来说，重要的是 MR 在细胞粘附和识别中发挥作用，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新型调节剂，并表明 MR 在 IL-4 信号下游发挥作用。该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 MR 无效小鼠的肌生成的各个方面。提出了一组 4 个具体目标来分析体外 MR 功能和作用机制（目标 1），分析体内肌肉再生过程中的 MR 功能（目标 2），确定 MR 是否与调节融合的已知途径相关（目标3）并鉴定其配体（目标4）。我们提出的研究将定义骨骼肌中调节成肌细胞融合的新途径。对 MR 的研究可能会带来在疾病、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。