人内源性逆转录病毒W家族env基因高表达导致神经细胞中胞内钙离子浓度升高的机制及作用研究

研究表明人内源性逆转录病毒（HERV）W家族env基因高表达与精神分裂症等疾病相关，而胞内钙离子浓度（[Ca2+]i）升高可引起环磷腺苷效应元件结合蛋白（CREB）的磷酸化，导致神经细胞异常，进而引发精神分裂症等疾病。我们的研究发现HERV-W env高表达可导致神经细胞中[Ca2+]i升高，并可导致磷酸化CREB表达水平升高。因此，我们拟研究HERV-W env高表达导致神经细胞中细胞膜钙转运系统调节胞内外Ca2+交换异常及胞内钙库释放Ca2+异常，揭示HERV-W env高表达导致的[Ca2+]i升高的机制；同时研究HERV-W env高表达导致[Ca2+]i的升高，进而引起磷酸化CREB表达水平升高的机制，探讨HERV-W env高表达导致的[Ca2+]i的升高在神经细胞中的作用。本项目将为揭示HERV-W env基因高表达在[Ca2+]i/钙信号通路异常中的作用，提供实验依据。

Recent studies 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. And there was also a relationship between the intracellular calcium concentration ([Ca2 +]i) and schizophrenia. While [Ca2+]i might lead to phosphorylation of cyclic adenosine monophosphate responsive element binding protein (CREB), resulting in abnormal nerve cells, and thus lead to many diseases such as schizophrenia.But the relationship among the overexpression of HERV, [Ca2 +]i and phosphorylation of CREB is still clear. Our data showed that the over-expression of env gene in nerve cells might contribute to the abnormity of several signal pathway. For example, the over-expression of env gene in nerve cells might lead to the expression of many factors （such as BDNF, S100B, CXCL10，KCNN3, etc）. And what's more, it is interesting that we found the over-expression of env gene in nerve cells might lead to the increase of [Ca2+]i and phosphorylation of CREB. While [Ca2+]i might be an important factor in the phosphorylation of CREB. From above on, based on the three National Natural Science Foundations and one stanley foundation of which are taken charge by the applicant, we will carry out "Study of the molecular mechanisms of increase of [Ca2+]i in neuro cell caused by the overexpression of HERV-W env" using molecular biology, bioinformatics and other biotechnologies.Therefore we will carry out this study from five areas: 1.The expression of HERV-W env increases [Ca2+]i in neuro cell; 2. The expression of HERV-W env leads to abnormal exchange between intracellular and extracellular Ca2+; 3. The expression of HERV-W env leads to the release of Ca2+ from endoplasmic reticulum calcium pool (release and re-absorption of Ca2+); 4. The expression of HERV-W env leads to the release of Ca2+ from Mitochondrial calcium pool (release and re-absorption of Ca2+);5. Study of the molecular mechanisms of the phosphorylation of CREB caused by the expression of HERV-W env in nerve cells. For this study, we will show the effect of the HERV-W env in the Ca2+ signal pathway in nerve cells. We will also reveal a new pathway of how HERV-W env causes diseases. And all these would provide new ideas about mechanism of how HERV-W env causes diseases and provide new ideas for treatment of some diseases.