人内源性逆转录病毒W家族包膜蛋白致神经炎症反应机制

Recent studies (include our data) showed that there was a close relationship between the HERV-W(human endogenous retrovirus) env and many diseases, such as schizophrenia, MS(Multiple Sclerosis), cancer, SLE(Systemic Lupus Erythematosus ), and so on. But the pathogenic mechanism is still not very clear. Our data showed that the expression of env gene in nerve cells might contribute to the expression of some inflammatory factors （such as IFN-β, IL-10, GM-CSF, CXCL10， etc）. And what's more, it is interesting that we found not only TLR4(Toll-like receptor 4), but also TLR3 pathway might be activated. And TLR3 might have some contribution to the expression of these inflammatory factors. From above on, based on the two National Natural Science Foundations and one stanley foundation which are completed by the applicant, we will carry out " Study of the molecular mechanisms of neurogenic inflammation caused by the HERV-W ENV protein in schizophrenia patients using molecular biology, bioinformatics and other biotechnologies. Therefore we will carry out this study from four areas: 1.The expression of HERV-W env activates the expression of inflammatory factors in the nerve cells; 2. The expression of HERV-W env leads to the inflammatory responses in small glica cells and T cells; 3. HERV-W env causes neurogenic inflammation through TLR3 pathway; 4. The Screening of HERV-W ENV protein encoding restricted CTL antigen epitopes, and study of the HERV-W ENV protein antigen epitope which causes the inflammatory response. For this study, we will show how the HERV-W env led the release of inflammatory cytokines. We will also reveal HERV-W env cause neurogenic inflammatory response in nerve cells through a new pathway. And all these would provide new ideas about mechanism of neurogenic inflammatory and provide new ideas for diagnosis and treatment of neurogenic inflammation related diseases.

文献报道人内源性逆转录病毒W家族（HERV-W）env基因激活与精神分裂症等疾病密切相关，其致病机理未明，我们发现在神经细胞中，HERV-W env基因表达可调控某些炎症因子（IFN-β等）的表达升高，并且该调控作用可能是通过天然免疫信号Toll样受体- - TLR3通路。因此，本项目将主要运用分子生物学、生物信息学等技术手段，开展人内源性逆转录病毒W家族包膜蛋白致神经炎症反应机制研究。研究HERV-W env基因激活表达调控神经细胞炎症因子释放以及导致小胶质细胞炎症反应和T细胞分化；探讨TLR3 通路在HERV-W env基因激活表达致神经炎症反应中的作用；筛选HERV-W ENV蛋白HLA限制性CTL抗原表位，研究引发炎症反应的HERV-W ENV蛋白抗原表位。该研究将揭示HERV-W env基因激活表达引发神经炎症反应的新通路- - TLR3通路，为神经炎症相关疾病的诊断与治疗提供新思路。

人内源性逆转录病毒W 家族（HERV-W）包膜蛋白（env ）基因激活与精神分裂症等疾病密切相关，并且HERV-W env蛋白可能会引发自身免疫，但机制未明。在本项目中，我们运用了分子生物学、生物信息学等技术手段，开展了HERV-W env蛋白致神经炎症反应机制的研究工作。在研究中，我们发现，HERV-W env 基因高表达可调控神经细胞中某些炎症因子（IFN-β、CRP 、IL-6等等）的释放以及表达升高，并且该调控作用可能是通过天然免疫信号Toll 样受体—— TLR3 通路；同时发现HERV-W env 基因高表达导致小胶质细胞炎症反应（如NO升高等）；我们进而运用生物学学手段筛选到了HERV-W ENV 蛋白HLA 限制性CTL 抗原表位，并进一步研究了引发炎症反应的HERV-W ENV 蛋白抗原表位，发现HERV-W ENV 蛋白引发免疫反应具有HLA-A2.1限制性。该研究揭示了HERV-W env 基因激活表达引发神经炎症反应的新通路——TLR3 通路，为神经炎症相关疾病的诊断与治疗提供新思路。