补体膜调控蛋白参与肿瘤抗体治疗耐药的分子机制

免疫监视和免疫清除是补体系统的重要功能，但此过程中宿主细胞如何应答和防御，进一步肿瘤细胞如何逃避补体杀伤并形成耐药的分子机制仍然是一个未知的重要科学问题，尽管补体膜调控蛋白（mCRPs）表达的上调可能是其中的关键因素，但对其分子调控机制还知之甚少。申请人最近首次系统地揭示了mCRPs分子CD59在转录水平上的分子调控机制及关键信号分子，即Sp1调节组成型CD59的表达，而NF-kB与CREB相互作用调节诱导型CD59的表达。本项目拟进一步研究其余两种mCRPs 分子CD46与CD55，利用GeneRacer、ChIP、EMSA、补体激活和裸鼠成瘤等实验手段，在分子、细胞及整体水平全面地阐述所有mCRPs参与宿主防御的调控网络及关键节点分子。然后以肿瘤抗体治疗的无应答与耐药形成为模型，探讨其中mCRPs的调控分子机制，发现潜在药物治疗靶点并筛选干预药物，为增敏肿瘤抗体治疗提供新思路新方法。

The immune surveillance and clearance are the important roles of complement system, however in which the molecular mechanisms of the immune response and host defense of autologous cells, further immune evasion and resistance development of cancer cells remains largely unknown. It is recognized that the up-regulations of membrane complement regulatory proteins (mCRPs) may be crucial during the above process. However, its molecular regulation mechanisms still remains elusive. The applicant has recently revealed the regulation mechanisms and the key signaling molecules for mCPR CD59 transcription, i.e. Sp1 modulates the constitutive expression of CD59, while NF-kB together with CREB modulates the inducible expression of CD59. In this proposal, we plan to extend our study for CD59 to the remaining mCRPs CD46 and CD55. Using GeneRacer, ChIP, EMSA, complement activation and xenografted nude mice, we will dissect their regulation mechanisms and further the key signaling molecules during the process of host defense in the levels of molecule, cell and animal. Moreover, the development of non-responsiveness and resistance to cancer antibody-based therapy will be exemplified in this study. We will dedicate to understand their underlying mechanisms and further find the key signaling molecules as the potential drug targets. In the end, we project to screen the druggable molecules for these targets; therefore, this study is hopeful to provide new insight into facilitating cancer antibody-based therapy.