人疱疹病毒6型立即早期(IE)蛋白在神经胶质瘤发生中的作用及机制研究

Glioma is the most common malignant primary brain tumors. The etiology of glioma is unclear till now. Our recent studies revealed that human herpesvirus 6 (HHV-6) is involved in the pathogenesis of malignant gliomas, however the exact mechanisms by which HHV-6 participates in the glioma formation are barely known. The immediate early (IE) genes are the first viral genes transcribed after infection. It has been found that IE proteins are transcription activators which posess important roles in the regulation of gene expression of host cells. Roles of HHV-6 IE proteins in the tumorigenesis of human malignant glioma and the underlying mechanisms will be investigated in this project. The study consists of three parts: (1) The correlation of the expression of IE proteins and glioma will be determined by clinical investigation. (2) Effects of IE proteins on the proliferation of glioma cells will be investigated and the underlying mechanisms will be explored. (3) Effects of IE proteins on cell transformation and tumor formation will be examined in vitro and in vivo. Results of this project may lead to a better understanding of the roles of HHV-6 IE proteins in the formation of giloma. Moreover, it would provide theoretical and experimental foundation not only for elucidating the molecular mechanisms of glioma formation, but also for the development of therapeutical and preventive vaccines for glioma.

神经胶质瘤（Glioma）是人类最常见的原发性恶性脑肿瘤，病因不清。本课题组前期研究发现人疱疹病毒6型（Human herpesvirus 6, HHV-6）感染和神经胶质瘤具有相关性。 HHV-6立即早期（immediate early，IE）蛋白是病毒最先表达的一类蛋白，研究发现IE蛋白是一种转录激活子，对宿主细胞基因的表达具有重要调控作用。本项目拟探讨HHV-6 IE蛋白在神经胶质瘤发生中的作用及机制。本研究包括三个方面：（1）临床水平研究HHV-6 IE蛋白表达与神经胶质瘤的相关性。（2）细胞水平研究IE蛋白对细胞增殖的影响及分子机制。（3）分别在体外和体内研究IE蛋白对神经胶质瘤细胞肿瘤形成能力的影响。本项目的研究结果不仅可以明确HHV-6 IE蛋白在神经胶质瘤中所起的作用及机制，而且可以为神经胶质瘤发病机制的阐明提供理论和实验依据，更为研制预防性和治疗性疫苗奠定基础。

神经胶质瘤是人类最常见的原发性恶性脑肿瘤，病因不清。本课题组前期研究发现人疱疹病毒6型（Human herpesvirus 6, HHV-6）感染和神经胶质瘤具有相关性。 HHV-6立即早期蛋白是病毒最先表达的一类蛋白，研究发现IE蛋白是一种转录激活子，对宿主细胞基因的表达具有重要调控作用。本研究包括三个方面：（1）收集神经胶质瘤患者样本，检测HHV-6感染以及IE蛋白表达与神经胶质瘤的相关性；（2）细胞水平研究U17蛋白对神经胶质细胞细胞增殖、侵袭和转移的影响及其分子机制。（3）通过裸鼠成瘤实验，体内探讨U17蛋白对神经胶质瘤肿瘤形成能力的影响。本研究结果证实人脑胶质瘤组织中存在HHV-6核酸及IE抗原，提示HHV-6 IE蛋白在脑胶质瘤的发生发展中起到一定的作用；以稳定表达立即早期基因U17的神经胶质瘤细胞U87为研究对象，研究表明立即早期基因U17表达可以明显促进神经胶质瘤细胞增殖、迁移和侵袭。裸鼠体内成瘤实验也证实U17稳定表达能够促进裸鼠皮下肿瘤组织的生长，肿瘤体积大于空载体对照组。mRNA转录谱芯片以及分子水平显示其作用机制可能与IL-8、SeprinB2、MMP3和Spink1表达上调， TIMP3表达下调有关。本项目的研究结果可以为HHV-6在神经胶质瘤病因发病过程的作用提供理论和实验依据，为研究预防性和治疗性疫苗奠定基础。