An investigation of radial glia as the source of ependymoma stem cells

放射状胶质细胞作为室管膜瘤干细胞来源的研究

• 批准号: 8073588
• 负责人: Richard James Gilbertson
• 金额: $ 30.96万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073588
• 关键词: Adult; Alleles; Anatomic Sites; Animal Model; Biological Assay; Breeding; CDKN2A gene; Cell Line; Cell physiology; Cells; Central Nervous System Neoplasms; Central Nervous System Part; Cerebellum; Cerebrum; Child; Childhood; Chromosome Mapping; Chromosome abnormality; Complex; Data; Development; Disease; Drug Delivery Systems; Embryonic Development; Embryonic Nervous System; Engineering; Environment; Ependymoma; Frequencies; Gene Expression; Gene Mutation; Gene Targeting; Genetic; Genomics; Human; In Vitro; Intracranial Neoplasms; Investigation; Knockout Mice; Label; Malignant Neoplasms; Maps; Mind; Minority; Molecular Profiling; Molecular Target; Mus; Mutation; NOTCH1 gene; Nervous system structure; Neuraxis; Neuroglia; Normal Cell; Oncogenes; Oncogenic; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Posterior Fossa; Predisposition; Property; Public Health; Radial; Research Personnel; Resistance; Resolution; Retroviridae; Sampling; Series; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Site; Solid Neoplasm; Sorting - Cell Movement; Source; Spinal; Spinal Neoplasms; Stem cells; Supratentorial; System; Testing; Therapeutic; Tumor Suppressor Genes; Vertebral column; Xenograft procedure; cancer stem cell; cell transformation; cohort; conventional therapy; effective therapy; gene function; hindbrain; in vivo; irradiation; knock-down; mouse model; multipotent cell; neural precursor cell; novel therapeutic intervention; programs; recombinase; research study; self-renewal; small hairpin RNA; tool; tumor; tumor initiation; validation studies

DESCRIPTION (provided by applicant): The recent discovery that many cancers are generated by small fractions cancer stem cells (CSC) suggests that targets of effective new treatments might be found among the mutations that initiate and maintain these cells. Ependymomas include a diverse group of tumors that arise throughout the central nervous system (CNS) of children and adults. These tumors often resist conventional treatments and are incurable in up to 40% of patients. Therefore, to identify potential new therapeutic approaches for ependymoma, we sort to identify the cell(s) of origin of this disease and the mutations that transform these into CSC. By comparing the gene expression profiles of tumors with those of the developing nervous system, we found that ependymomas from the different parts of the CNS share the gene expression profiles of neural precursor cells, termed radial glia (RG), in the corresponding region of the embryonic nervous system. We showed also that ependymomas are propagated and maintained by CSC that are remarkably similar to RG and that ependymomas from the different parts of the CNS contain anatomic site-specific chromosomal alterations. Thus, we hypothesize that RG in the different parts of the CNS are cells of origin of ependymoma and are predisposed to acquire distinct gene mutations that transform these cells into ependymoma CSC. To test our hypothesis we propose a series of highly-integrated genomic and CSC studies that will employ mouse models and the largest cohort of human ependymoma tumors collated to date. We propose to: 1) Use the 500K single nucleotide polymorphism mapping array profiles that we have generated already from 230 samples of ependymoma to identify candidate oncogenes and tumor suppressor genes (TSG) of this disease. 2) Activate candidate oncogenes and knock-down candidate TSG in RG from the different regions of the CNS to determine if these cells are susceptible to be transformed into CSC. Assessment of CSC properties will include unbridled self-renewal and tumor initiating capacity. 3) Engineer in RG of a genetic mouse model, concurrent activation of Notchl signaling and Ink4a/Arf deletion that we have observed in human intracranial ependymoma. Relevance to Public Health: There is a desperate need for effective new treatments of ependymoma. By defining the cell of origin of ependymoma and the mutations that transform these cells, the Aims of this proposal will bring about a profound increase in understanding of this disease and identify molecular targets for new treatments.

描述（由申请人提供）：最近发现许多癌症是由小部分癌症干细胞（CSC）产生的，这表明有效的新治疗目标可能会在启动和维持这些细胞的突变中找到。室管膜瘤包括在儿童和成人的中枢神经系统 (CNS) 中出现的多种肿瘤。这些肿瘤通常对常规治疗有抵抗力，并且高达 40% 的患者无法治愈。因此，为了确定室管膜瘤的潜在新治疗方法，我们确定了这种疾病的起源细胞以及将这些细胞转化为 CSC 的突变。通过比较肿瘤与发育中神经系统的基因表达谱，我们发现中枢神经系统不同部位的室管膜瘤具有胚胎神经系统相应区域神经前体细胞（称为放射状胶质细胞（RG））的基因表达谱。我们还表明，室管膜瘤是由 CSC 传播和维持的，与 RG 非常相似，并且来自 CNS 不同部分的室管膜瘤包含解剖位点特异性染色体改变。因此，我们假设中枢神经系统不同部位的 RG 是室管膜瘤的起源细胞，并且易于获得不同的基因突变，将这些细胞转化为室管膜瘤 CSC。为了检验我们的假设，我们提出了一系列高度整合的基因组和 CSC 研究，这些研究将采用小鼠模型和迄今为止整理的最大的人类室管膜瘤队列。我们建议：1) 使用我们从 230 个室管膜瘤样本中生成的 500K 单核苷酸多态性映射阵列图谱来识别该疾病的候选癌基因和抑癌基因 (TSG)。 2) 激活中枢神经系统不同区域RG中的候选癌基因并敲除候选TSG，以确定这些细胞是否容易转化为CSC。 CSC 特性的评估将包括不受限制的自我更新和肿瘤启动能力。 3) 基因小鼠模型的RG工程，我们在人颅内室管膜瘤中观察到Notch1信号传导和Ink4a/Arf缺失同时激活。与公共卫生的相关性：迫切需要有效的室管膜瘤新疗法。通过定义室管膜瘤的起源细胞和转化这些细胞的突变，该提案的目标将深刻增进对这种疾病的了解，并确定新治疗的分子靶点。