PICK1调控TLR4/MyD88/ERK通路在炎症诱导胶质瘤发生发展中的作用机制

Glioma is the most common neurological malignancy. Studies have shown that the occurrence and development of glioma is related to inflammation. The development of glioma may be induced by the activation of NF-κB through the Toll-like receptor 4 (TLR4), while the specific mechanism is not clear. In our group, we have studied the protein interacting with C-kinase 1 (PICK1) and receptor transport, and we found that the expression of PICK1 in glioma cells was significantly decreased. After restoring the expression of PICK1, the number of TLR4 in the membrane of glioma cells was down-regulated and the cell proliferation was inhibited. The researches on glial cells have shown that TLR4 regulates the expression of inflammatory factor mainly through the MEK / ERK pathway. The PICK1 knockout mice showed higher rate of tumor formation than control model. Based on these results, we hypothesize that the PICK1 participate in the transport of TLR4 by binding to TLR4 in glioma cells, and then regulate the expression of TLR4 / MyD88 /ERK signaling pathway to affect the development of glioma. This proposal aims to study the specific mechanism of PICK1-TLR4 interaction, and TLR4/MyD88 pathway in the occurrence and development of glioma, by setting up an oncogene-activated mouse glioma model with knockout of PICK1. The study will also focus on the aspects of molecule, cell, and tissue, and will provide a theoretical basis for the prevention and treatment of glioma.

胶质瘤是最常见神经系统恶性肿瘤，有研究表明胶质瘤的发生发展与炎症相关，通过胶质瘤中Toll样受体4（TLR4）激活NF-κB，而促进胶质瘤的发展，但具体机制尚不明确。我们在研究PICK1与受体运输中发现胶质瘤中PICK1表达量明显降低，在恢复PICK1表达后，胶质瘤细胞表面TLR4数量明显下调，细胞增殖受抑；同时胶质细胞研究表明TLR4主要通过MEK/ERK通路调控炎症因子表达；小鼠胶质瘤模型也已证实在PICK1敲除小鼠中成瘤率明显增加。据此我们提出假设，胶质瘤细胞中PICK1通过与TLR4结合影响TLR4的运输，从而调控TLR4/MyD88/ERK信号通路影响胶质瘤的发生发展。本项目拟通过PICK1条件敲除等小鼠制备癌基因激活胶质瘤模型，结合分子、细胞和组织等层次对PICK1与TLR4的作用机制，及调控TLR4/MyD88通路影响胶质瘤发生发展的具体机制，为胶质瘤的防治提供理论依据。

胶质瘤是最常见神经系统恶性肿瘤，有研究表明胶质瘤的发生发展与炎症相关，通过胶质瘤中Toll样受体4（TLR4），而促进胶质瘤的发展，但具体机制尚不明确。我们在PICK1介导的肿瘤发展机制研究发现:PICK1是肿瘤EMT进程的重要分子标志物，与经典EMT相关分子具有联合诊断意义；PICK1/TLR4在胶质瘤发生发展中的协同，PICK1能够与TLR4结合介导TLR4上下膜，影响TLR4/MYD88/ERK炎症信号通路。在了解PICK1在胶质瘤作用的基础上，我们构建了PICK1分子多肽，连接特异性穿膜肽后，利用分子生物学技术在分子、细胞和形态等层次治疗胶质瘤，为胶质瘤的防治提供理论依据。