组蛋白H2A.Z在神经胶质瘤发生发展中的生物学机制研究

Glioma arising from glia cells is the most common brain tumor. Surgery, radiation therapy and alkylating agents such as temozolomide are the primary treatments for glioma patients. However, even with the treatment, the median survival time of patients with high grade glioma is still less than 14 months. Chemo- and radio- resistance, tumor recurrence are the major barriers in the treatment of glioma patients. Identifying novel therapeutic targets which contribute to glioma tumorigenesis and overcome these barriers are of great interest. Recently, therapeutic approaches targeting epigenetic factors become a novel frontier in cancer therapy. Epigenetic modulation refers to the alteration of gene expression without changes of DNA sequences. Since epigenetic regulation is able to alter the expression of a group of genes simultaneously, therapeutic approaches based on epigenetic reprogramming are more powerful than traditional treatment. In addition, epigenetic abnormalities are frequently found in cancer patients. Further, epigenetic drug in combination with traditional anti-cancer drugs provides synergistic effect and overcomes drug resistance. Cancer stem cells are a subpopulation of tumor cells which can self-renew and differentiate into diverse tumor cells. Usually cancer stem cells resist chemotherapy and radiation therapy and are involved in tumor initiation, progression and recurrence. In this proposal, we are going to use glioma stem cells isolated from glioma patients and investigate the tumorigenesis of glioma and underlying mechanism of radiation resistance. We will focus on epigenetic regulation of stemness like properties and radiation resistance in glioma stem cells, employ state of the art technologies such as genome-wide sequencing and identify a novel therapeutic target for glioma drug development.

神经胶质瘤是源于神经胶质细胞的常见脑部肿瘤，因其恶性程度高且药物和辐射耐受性的特点，胶质母细胞瘤病人平均生存期少于14个月，因此研究胶质瘤发生机制、寻找治疗靶点及克服治疗屏障具有重要意义。近来表观遗传因子靶向治疗已经成为肿瘤治疗的新前沿，传统抗癌药与表观遗传靶向药联合应用能克服肿瘤治疗中的化学耐药性。肿瘤干细胞作为肿瘤细胞的亚群，具有自我更新和肿瘤分化潜力，并且具有很强的放疗和化疗抵抗性，极易使肿瘤复发。我们前期工作发现组蛋白变异体H2A.Z在胶质瘤干瘤细胞中高表达可抑制其分化并增强其辐射耐受性，提示H2A.Z与胶质瘤有功能联系。因此本课题将从神经胶质瘤病人中分离神经胶质瘤干细胞，研究胶质瘤发生与放疗拮抗的潜在机制，聚焦神经胶质瘤干细胞干性维持和放疗拮抗中的表观遗传调控，采用全基因组测序等方法，探讨H2A.Z在神经胶质瘤发生中的生物学机制，为神经胶质瘤的药物研发提供一个全新的治疗靶点。