基于蛋白4.1R上调的PCNP抑制与重症肌无力发生的关联性

Myasthenia gravis (MG) is an autoimmune disease of unknown cause and mechanism. Protein 4.1R is an important memberane skeletal component, regulate the cellular proliferation and division and take a key role as a signal transitional station between cellular adhesion factors and intracellular signal transduction. Prelimanary experiments showed that the expression level of mRNA of protein 4.1R is significantly different between proliferative type and control and between thymoma plus atrophic type and control. To fully understand the function of 4.1R in MG, we aim to explore the expressison of protein 4.1R in each kind of cells in thymus from MG patients and its subcellular location in cells. Then we would choose cells of higher expresion as the model of gene silencing and over-expression. The third method we used is animal model of MG by giving protein 4.1R or its inhibitor(siRNA) into mice with MG. Finally the study is done in 4.1R knockout mice by administering 4.1R protein. It is expected that we would find the role of higher expression of protein 4.1R, the signaling pathway and involving upstream and downstream molecules for protein 4.1R and the new idea and method of diagnosis, therapy and prevention for MG. We are the first group who find that protein 4.1R in thymus of patients with MG can induce deficiency of antigen presentation by DC and the folloing T cell disorder and finally result in the symptoms of MG.

重症肌无力（MG）机制不清。蛋白4.1R作为重要的膜骨架成分，参与调节细胞分裂增殖，在细胞粘附因子和细胞内信息传导中发挥“信号中转站”的关键作用。预实验表明MG组与对照组相比，增生型MG组胸腺组织中蛋白4.1R表达上调；胸腺瘤和萎缩型MG组胸腺组织中蛋白4.1R mRNA的表达升高;DC内蛋白4.1R过表达能抑制核蛋白PCNP，推测蛋白4.1R与PCNP互作而诱发MG。拟探讨蛋白4.1R在MG患者胸腺内细胞和亚细胞中的分布；进一步探讨在肌肉细胞C2C12、大鼠膈肌无力和MG动物模型上，蛋白4.1R蛋白对骨骼肌细胞的影响；探讨蛋白4.1R基因敲除小鼠中蛋白4.1R在MG发生中的整体作用；探讨蛋白4.1R过表达和沉默在DC细胞中的作用，特别是与PCNP的关系。本项目首次提示MG胸腺中蛋白4.1R上调造成DC抗原递呈障碍和免疫异常;蛋白4.1R可直接影响肌肉收缩蛋白，引起MG。

重症肌无力（MG）的发生机制尚不清。蛋白4.1R作为重要的膜骨架成分，参与调节细胞分裂增殖，在细胞粘附因子和细胞内信息传导中发挥“信号中转站”的关键作用。实验表明MG组与对照组相比，增生型患者胸腺中蛋白4.1R表达上调；胸腺瘤和萎缩型MG组胸腺组织中蛋白4.1R mRNA的表达升高;DC内蛋白4.1R过表达能抑制核蛋白PCNP，推测蛋白4.1R与PCNP互作而诱发MG。为进一步研究详细的分子机制， 我们探讨了蛋白4.1R在MG患者胸腺内细胞和亚细胞中的分布；在肌肉细胞C2C12、大鼠膈肌无力和MG动物模型上，探讨了蛋白4.1R蛋白对骨骼肌细胞的影响；同时过表达和沉默蛋白4.1R，了解其在DC细胞中的作用，特别是与PCNP的关系。本项目的意义在意首次提示MG胸腺中蛋白4.1R上调造成DC抗原递呈障碍和免疫耐受，同时蛋白4.1R可直接影响肌肉收缩蛋白引起MG症状。初步揭示了蛋白4.1R与MG的关系，为自身免疫疾病发生机制和治疗提供了新思路。