Reprogramming the Human Glioma Genome

 描述(申请人提供)：恶性胶质瘤，最致命的神经疾病在大脑中，基本上是不可治愈的，因为他们的快速增长和非常侵袭性的性质。消除脑瘤的一种范式转换治疗方法是改变胶质瘤细胞的命运，使它们是非增殖性和非侵袭性的。我们之前已经证明，病毒介导的两种转录因子的表达可以非常高效地将人成纤维细胞直接转化为神经元。出乎意料的是，我们的初步结果还显示，人类恶性胶质瘤细胞可以非常有效地转化为神经元样细胞，不再增殖或侵袭。即使是被转导但尚未转换命运的细胞也停止了增殖，这表明这些因素在控制人类胶质瘤细胞的行为方面发挥了主导作用。我们的初步结果进一步表明，大多数体内转化的细胞不能在成人脑环境中存活。基于这些非常令人兴奋的发现，我们建议梳理出人类胶质瘤细胞强制终末分化的分子机制，这是由两个转录因子协同作用所介导的。我们将特别关注转录组、环路、全球染色质结构和重新编程过程中的表观遗传修饰。这项研究的结果可能会导致识别控制人类胶质瘤细胞行为的结点，这可能是开发针对最致命的脑疾病-胶质母细胞瘤的新疗法的靶点。

 DESCRIPTION (provided by applicant): SUMMARY Malignant gliomas, the most deadly neurological disease in the brain, are essentially incurable due to their rapid growth and very invasive nature. One paradigm-shifting therapeutic approach to eliminating brain tumors is to change the fate of glioma cells so that they are non-proliferative and non-invasive. We previously showed that virus-mediated expression of two transcription factors directly converts human fibroblasts to neurons with extremely high efficiency. Unexpectedly, our preliminary results also revealed that malignant human glioma cells can be very efficiently converted to neuron-like cells, which are no longer proliferative or invasive. Even the cells that are transduced but not yet fate-converted stopped proliferation, indicating a dominant role for these factors in governing the behavior of human glioma cells. Our preliminary results further show that majority of the in vivo converted cells cannot survive in the adult brain environment. Based on these very exciting findings, we propose to tease out the molecular mechanism underlying forced terminal differentiation of human glioma cells that is mediated by a synergistic action of two transcription factors. We will specifically focus on transcriptome, cistrome, global chromatin structure and epigenetic modifications during the reprogramming process. Results from this study may lead to the identification of nodal points controlling the behavior of human glioma cells, which can be targeted for developing novel therapeutics against the most deadly brain disease-glioblastoma.