Reprogramming the Human Glioma Genome

重新编程人类神经胶质瘤基因组

• 批准号: 9064865
• 负责人: Chun-Li Zhang
• 金额: $ 24.28万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064865
• 关键词: ASCL1 gene; Adult; BETA2 protein; Behavior; Behavior Control; Binding; Binding Sites; Boxing; Brain; Brain Diseases; Brain Neoplasms; Cells; ChIP-seq; Chromatin Structure; DNA Binding; DNA Methylation; Data; Data Set; Deoxyribonuclease I; Development; Ectopic Expression; Enhancers; Environment; Epigenetic Process; Fibroblasts; Gene Expression; Gene Expression Profiling; Genes; Genome; Glioblastoma; Glioma; Goals; Grant; Health; Human; Lead; Maintenance; Malignant - descriptor; Malignant Glioma; Mediating; Modification; Molecular; Mus; Nature; Neurons; Nodal; Nucleic Acid Regulatory Sequences; Phenotype; Process; Research; Role; SOX11 gene; Signal Pathway; Site; Therapeutic; Time; Transplantation; Tumor Cell Invasion; Virus; Work; base; cell behavior; cell type; cellular transduction; chromatin remodeling; combinatorial; effective therapy; genome-wide; in vivo; neoplastic cell; nervous system disorder; neurotrophic factor; new therapeutic target; novel therapeutics; promoter; rapid growth; sex; synergism; transcription factor; transcriptome; transcriptome sequencing; tumor

 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.

 描述（由申请人提供）： 概要 恶性神经胶质瘤是大脑中最致命的神经系统疾病，由于其快速生长和极具侵袭性，本质上是无法治愈的。消除脑肿瘤的一种范式转变的治疗方法是改变神经胶质瘤细胞的命运，使它们不增殖和非侵袭。我们之前表明，病毒介导的两种转录因子的表达能够以极高的效率直接将人类成纤维细胞转化为神经元。出乎意料的是，我们的初步结果还表明，恶性人胶质瘤细胞可以非常有效地转化为不再增殖或侵袭的神经元样细胞。即使是已转导但尚未发生命运转换的细胞也停止了增殖，表明这些因素在控制人类神经胶质瘤细胞的行为中发挥着主导作用。我们的初步结果进一步表明，大多数体内转化细胞无法在成人大脑环境中存活。基于这些非常令人兴奋的发现，我们建议梳理出人类神经胶质瘤细胞强制终末分化的分子机制，该机制是由两个转录因子的协同作用介导的。我们将特别关注重编程过程中的转录组、顺反组、整体染色质结构和表观遗传修饰。这项研究的结果可能有助于识别控制人类神经胶质瘤细胞行为的节点，从而可以针对开发针对最致命的脑部疾病——胶质母细胞瘤的新疗法。