Regulation of Asymmetric Cellular Division in Glioma Stem Cells

胶质瘤干细胞不对称细胞分裂的调节

• 批准号: 8617814
• 负责人: DANIEL J BRAT
• 金额: $ 37.92万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617814
• 关键词: Animal Model; Automobile Driving; Behavior; Biological; Biology; Brain; Brain Neoplasms; Cell Cycle; Cell division; Cell physiology; Cells; Cellular Structures; Computer Simulation; Data; Daughter; Down-Regulation; Drosophila genus; Drosophila melanogaster; Equilibrium; Excision; Genes; Genetic; Glioblastoma; Glioma; Growth; Homologous Gene; Human; Hypoxia; Lead; Lentivirus Vector; Literature; Loss of Heterozygosity; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Molecular; Mus; Mutate; Neoplasms; Nervous system structure; Neuroblastic Cell; Neuroglia; Neurons; Pathway interactions; Pattern; Primary Brain Neoplasms; Property; Proteins; Proto-Oncogene Proteins c-myc; Recurrence; Regulation; Sampling; Specimen; Staging; Stem cells; The Cancer Genome Atlas; Therapeutic; Tumor Suppressor Genes; Tumorigenicity; Undifferentiated; Xenograft Model; base; c-myc Genes; daughter cell; glioma cell line; in vitro activity; in vivo; mouse model; mutant; neoplastic; neoplastic cell; nestin protein; neuroblast; pluripotency; protein expression; public health relevance; relating to nervous system; segregation; self-renewal; small hairpin RNA; stem; stem cell differentiation; stem cell division; tumor progression

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common and most malignant primary brain tumor. Recent studies suggest that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), may govern the biologic behavior of GBM. GSCs have properties of self-renewal, pluripotency and high tumorigenicity. They have thus far been identified by the expression of specific markers, such as CD133, Sox2 and nestin, yet molecular mechanisms responsible for stem-like behavior have not been clearly defined, nor have regulators of the stem/non-stem equilibrium. This proposal aims to define molecular mechanisms that confer stem-like qualities to GSCs and enriches their presence in GBMs. Pathways that direct asymmetric cellular division and stem-like behavior in the Drosophila melanogaster nervous system have been well described and may provide clues to stem cell properties and the stem/non-stem balance in malignant gliomas. The Drosophila brain tumor (brat) gene product regulates asymmetric cell division through its segregation into the daughter cell destined for differentiation, where it functions to translationally repress Myc. In brat mutants, asymmetric division and neural differentiation do not occur, leading to a massively enlarged larval brain containing highly proliferative undifferentiated neuroblastic cells with neoplastic properties. The human homolog of Drosophila brat, Trim3, shows allelic loss in over 25% of GBMs and reduced expression in nearly all. In the current proposal, we hypothesize that reduced expression of Trim3, or its interacting proteins, is critical in defining stem-like properties in human GSCs by favoring a loss of asymmetric cell division and enriching the stem cell compartment. We propose to investigate Trim3 in human gliomas in order to determine if its expression is downregulated in human GBMs; if Trim3 regulates c-Myc protein expression and activity in vitro and in vivo; if Trim3 regulates stem like properties of human in GBM neurosphere cultures and GBM resection specimens; if genetic and hypoxic mechanisms regulate Trim3 during tumor progression; and if Trim3 regulates the in vivo growth properties of GBM in animal models.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见和最恶性的原发性脑肿瘤。最近的研究表明，一小部分肿瘤细胞，称为神经胶质瘤干细胞（GSC），可能控制 GBM 的生物学行为。 GSCs具有自我更新、多能性和高致瘤性的特性。迄今为止，它们已通过特定标记（例如 CD133、Sox2 和巢蛋白）的表达来鉴定，但负责类茎行为的分子机制尚未明确定义，也没有茎/非茎平衡的调节因子。该提案旨在定义赋予 GSC 类似干细胞品质并丰富其​​在 GBM 中存在的分子机制。果蝇神经系统中指导不对称细胞分裂和干细胞样行为的途径已得到充分描述，可能为恶性胶质瘤中干细胞特性和干/非干细胞平衡提供线索。果蝇脑肿瘤 (brat) 基因产物通过分离到用于分化的子细胞中来调节不对称细胞分裂，在子细胞中它的功能是翻译抑制 Myc。在幼虫突变体中，不发生不对称分裂和神经分化，导致幼虫大脑大量增大，其中含有具有肿瘤特性的高度增殖的未分化神经母细胞。果蝇 brat 的人类同源物 Trim3 在超过 25% 的 GBM 中显示出等位基因丢失，并且几乎所有 GBM 中的表达均降低。在当前的提议中，我们假设 Trim3 或其相互作用蛋白的表达减少，通过促进不对称细胞分裂的丧失和丰富干细胞区室，对于定义人类 GSC 中的干细胞样特性至关重要。我们建议研究人类神经胶质瘤中的 Trim3，以确定其表达在人类 GBM 中是否下调； Trim3 是否在体外和体内调节 c-Myc 蛋白表达和活性； Trim3 是否调节 GBM 神经球培养物和 GBM 切除标本中人类的干细胞特性； Trim3在肿瘤进展过程中是否受到遗传和缺氧机制的调节； Trim3 是否调节动物模型中 GBM 的体内生长特性。