LRP4在DMD肌肉再生障碍中的作用及分子机制

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. Muscle regeneration defects is the characteristics of the DMD, however, the molecular mechanism is unclear. Previously, we found that LRP4, a member of low-density lipoprotein receptor-related protein family, was up-regulated in mdx mice, which is the classic DMD model mouse. Then, we constructed a muscle specific over expression of LRP4 mice (HSA-LRP4), we found the muscle regeneration capacity was reduced and the proliferation of satellite cells was inhibited in HSA-LRP4 mice. Therefore, we hypothesized that over expression of LRP4 lead to muscle regeneration defects in DMD. In this study, first, we will investigate molecular mechanisms underlying over expression of LRP4 inhibit muscle regeneration. Meanwhile, we will study which domain of LRP4 was essential and functional in the process. Finally, we will investigate whether the dystrophic phenotype and function defects of satellite cells will be rescued by knockdown LRP4 in mdx mice, further confirmed the role of LRP4 on muscle regeneration in DMD. The study will enrich the research on molecular mechanism of regulation of DMD, and to provide scientific clues and basis for the clinical treatment of muscle damage and muscle atrophy.

杜氏肌萎缩（DMD）是进行性肌萎缩中发病率最高的类型之一。肌肉再生能力低是该病的一个重要特征，但其分子机制尚不清楚。我们前期预实验发现DMD经典模型鼠mdx小鼠肌肉低密度脂蛋白受体相关蛋白家族成员LRP4基因表达升高，通过构建肌肉特异性LRP4高表达小鼠（HSA-LRP4），发现该鼠肌肉再生能力降低，再生过程中肌卫星细胞增殖受到抑制。我们因此推测LRP4高表达是导致DMD中肌肉再生能力降低原因。本项目拟首先利用HSA-LRP4小鼠研究高表达LRP4抑制肌肉再生的分子机制，同时确定其发挥功能的重要结构域；然后我们将研究在mdx小鼠上降低LRP4水平是否修复该鼠肌萎缩坏死及肌卫星细胞功能受损表型，更进一步证实DMD中LRP4对肌肉再生能力的调节。本项目结果将丰富DMD的病理机制研究，从而为临床上治疗肌萎缩和肌损伤等病症提供科学线索和依据。

杜氏肌萎缩（DMD）是进行性肌萎缩中发病率最高的类型之一。肌肉再生能力低和神经肌肉接头形态功能发生病变是该病的重要特征，但其分子机制尚不清楚。本项目研究了神经肌肉接头经典信号通路Agrin-LRP4-MuSK在DMD的作用及其机制。取得以下结果：1）肌肉特异性高表达LRP4显著抑制肌肉再生 2）在DMD模型鼠肌肉高表达LRP4改善神经肌肉接头功能 3）在小鼠体内诱导产生Agrin抗体能够导致重症肌无力表型 4）高表达DEC1抑制肌肉卫星细胞增殖分化。本项目结果将丰富DMD和重症肌无力的病理机制研究，从而为临床上治疗肌萎缩和肌损伤等病症提供科学依据，也将丰富Agrin-LRP4信号通路的功能研究。

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