Mediators of EWS/FLI Oncogenesis in Ewing's Sarcoma

尤文肉瘤中 EWS/FLI 肿瘤发生的介质

• 批准号: 6730975
• 负责人: William A May
• 金额: $ 26.78万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730975
• 关键词: Ewing's tumor; Retroviridae; SCID mouse; antisense nucleic acid; carcinogenesis; complementary DNA; enzyme activity; expression cloning; human tissue; neoplasm /cancer genetics; pediatric neoplasm /cancer; recombinase; transcription factor

DESCRIPTION (Investigator's abstract): A wide variety of human malignancies are associated with aberrant transcription factors in a high proportion of cases. In none of these instances is that association stronger than that found between the EWS/FLI (and other EWS/ets) chimeric transcription factor and the Ewing Family Tumors, Ewing's Sarcoma and peripheral Primitive Neuroectodermal Tumor (PNET). Multiple lines of evidence demonstrate that the biology of these chimeric transcription factors is central to the development and sustenance of these tumors. The key to understanding the biology of these unique proteins is to elucidate those targets of biologic consequence which are aberrantly regulated as a result of EWS/FLI and its congeners. This proposal will accomplish this goal though the use of an expression cloning approach in which biologically relevant genes that act downstream of EWS/FLI will be isolated and identified. Using the MaRX expression cloning system and a model transformation system, genes mediating the in vitro phenotype of EWS/FLI will be elucidated. Genetic variables in the system will be tightly controlled. Measures will be taken to screen out false positives as well as to enhance the ability to detect important targets that may be expressed at low levels. Through a variety of measures, the role of these downstream effectors in human tumors will then be established. The in vivo phenotype of EWS/FLI will also be investigated. A population-based cycle cloning strategy will be used in an in vivo tumorigenesis assay. Those species that are enriched in this system will be characterized for their involvement in human tumorigenesis. Finally, an in vitro assay system will be used to isolate genes that work in concert with EWS/FLI to permit EWS/FLI transformability. Data from these studies will enhance our understanding of this enigmatic family of human tumors. This understanding will provide a valuable paradigm for the study of the wide array of malignancies that are associated with aberrant transcription factors.

描述（研究者摘要）：多种人类恶性肿瘤 在大部分病例中与异常转录因子有关。 在这些情况下，这种关联都没有比之间发现的关联更强。 EWS/FLI（和其他 EWS/ets）嵌合转录因子和 Ewing 家族肿瘤、尤文氏肉瘤和外周原始神经外胚层肿瘤 （PNET）。多种证据表明这些物质的生物学特性 嵌合转录因子对于发育和维持至关重要 这些肿瘤。了解这些独特蛋白质生物学的关键是 阐明那些异常的生物学后果目标 由于 EWS/FLI 及其类似物而受到监管。该提案将 通过使用表达克隆方法来实现这一目标，其中 作用于 EWS/FLI 下游的生物学相关基因将被分离并 确定。使用MaRX表达克隆系统和模型转换 系统，介导 EWS/FLI 体外表型的基因将被阐明。 系统中的遗传变量将受到严格控制。措施将是 旨在筛选误报并增强检测能力 可能以较低水平表达的重要目标。通过各种 措施，这些下游效应器在人类肿瘤中的作用将是 已确立的。还将研究 EWS/FLI 的体内表型。一个 基于群体的循环克隆策略将用于体内 肿瘤发生测定。那些在该系统中富集的物种将 其特征在于它们参与人类肿瘤发生。最后，一个在 体外测定系统将用于分离与协同作用的基因 EWS/FLI 允许 EWS/FLI 转换。这些研究的数据将 增强我们对这个神秘的人类肿瘤家族的了解。这 理解将为广泛的研究提供一个有价值的范式 与异常转录因子相关的恶性肿瘤。