重症肌无力(MG)是主要由乙酰胆碱受体(AChR)抗体介导的神经肌接头信息传递障碍性疾病，AChR的内化异常和聚集障碍是肌无力发生的重要机制。我们的研究发现碳酸酐酶III(CA3/CAR3)在MG患者骨骼肌中特异性减少，且CAR3减少可加重EAMG小鼠肌无力症状并有伴侣蛋白辅助的选择性自噬(CASA)增加。进一步观察到CASA增加可加重AChR内化并抑制AChR聚集通路中MuSK磷酸化。鉴此，我们认为CASA可通过加速AChR内化和抑制AChR的聚集促进肌无力的发生。本项目拟利用Car3-/-的EAMG小鼠模型和骨骼肌细胞，研究CAR3对CASA发生的调控机制、CASA通过抑制MuSK稳定性和磷酸化调控AChR聚集、及CASA调控AChR内化和结构破坏的机制，阐明CASA调控AChR聚集和内化在MG发病中的作用机制，并探讨靶向调控CASA在治疗MG中的应用潜能，为MG的机制研究提供新靶点。

Myasthenia gravis (MG) is a neuromuscular junction transmission disorder, mainly mediated by autoantibody against acetylcholine receptor (AChR) in postsynaptic endplates. Impaired AChR clustering and dysregulated endocytosis are key mechanisms during the pathogenesis of myasthenia gravis. Our previous studies showed a protein carbonic anhydrase III (CA3 for human, CAR3 for mouse) is insufficiency in skeletal muscle of MG patients. In addition, inhibition of CAR3 in experimental autoimmune myasthenia gravis (EAMG) mice exacerbated symptoms of muscle weakness, and also enhanced chaperon-assisted selective autophagy (CASA) in skeletal muscle. Further research observed that enhancement of CASA can accelerated endocytosis of AChR and inhibit muscle specific kinase (MuSK) phosphorylation which is critical in AChR clustering. So we hypothesis that in skeletal muscle CASA contributes to pathogenesis of myasthenia gravis through acceleration of AChR endocytosis and inhibition of AChR clustering. But the modulation mechanisms are not clear. This project will explore the mechanisms of how CASA is happened and regulated by CAR3, the role of CASA in the regulation of MuSK complex stability and phosphorylation in the regulation of AChR clustering, as well as the details of CASA regulating AChR endocytosis. And further we would like to explore the potential intervention targeting to CAR3 and CASA in treatment of myasthenia gravis and other neuromuscular junction disorders.