Normal and Neoplastic Growth Regulation in the Brain

大脑中的正常和肿瘤生长调节

• 批准号: 7064825
• 负责人: SUZANNE J BAKER
• 金额: $ 177.28万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064825
• 关键词: brain neoplasms; cell growth regulation; medulloblastoma; neoplasm /cancer genetics; neoplastic process

The goal of this program project is to increase understanding of the molecular basis of normal and neoplastic growth in the developing brain. The ultimate objective is to use this knowledge to devise novel strategies for treatment of medulloblastoma, the most common pediatric malignancy of the central nervous system. This objective is being pursued through four interactive projects that investigate the role of different signaling pathways in the growth of the central nervous system and brain tumors supported by an Administrative Core and a Bioinformatics and Microarray Core. In Project 1, T. Curran utilizes a mouse model of medulloblastoma to investigate the role of the Shh/Ptc/Smo pathway in tumorigenesis. This involves the use of pharmacological inhibitors in cell culture and in vivo, a molecular characterization of Gill and comparison of the epigenetic and genetic alterations underlying medulloblastoma by nuclear transplant into oocytes. In Project 2, P. McKinnon investigates the contribution of DNA damage signaling to medulloblastoma formation. This project is based on the characterization of a novel model for medulloblastoma in mice lacking DNA Ligase IV and p53. This analysis will involve comparison of gene expression microarray profiles of the different medullobalstomas in the program. In Project 3, R. Gilbertson is investigating the role of ERBB2 in human medulloblastoma. This involves the characterization of human medulloblastoma cell lines using pharmacological and gene expression microarray approaches. The information will be compared to the data obtained on mouse models and an existing database of human brain tumors. A mouse model will be created in which ERBB2 is expressed in cerebellar granule neurons. In Project 4, S. Baker is studying the role of the Pten signaling pathway in growth regulation in the brain. This includes characterization of the function of downstream effector genes in the cerebellum and the creation of new mutant mouse strains to investigate its contribution to growth, proliferation and tumorigenesis.

该计划项目的目标是增进对发育中大脑正常和肿瘤生长的分子基础的了解。最终目标是利用这些知识来设计治疗髓母细胞瘤的新策略，髓母细胞瘤是中枢神经系统最常见的儿科恶性肿瘤。这一目标正在通过四个互动项目来实现，这些项目研究不同信号通路在中枢神经系统和脑肿瘤生长中的作用，并由管理核心和生物信息学和微阵列核心支持。在项目 1 中，T. Curran 利用髓母细胞瘤小鼠模型来研究 Shh/Ptc/Smo 通路在肿瘤发生中的作用。这涉及在细胞培养和体内使用药理学抑制剂、Gill 的分子表征和比较 通过核移植到卵母细胞中，研究髓母细胞瘤的表观遗传和遗传改变。在项目 2 中，P. McKinnon 研究了 DNA 损伤信号传导对髓母细胞瘤形成的影响。该项目基于缺乏 DNA 连接酶 IV 和 p53 的小鼠髓母细胞瘤新模型的表征。该分析将涉及程序中不同髓母细胞瘤的基因表达微阵列图谱的比较。在项目 3 中，R. Gilbertson 正在研究 ERBB2 在人类髓母细胞瘤中的作用。这涉及使用药理学和基因表达微阵列方法来表征人类髓母细胞瘤细胞系。这些信息将与在小鼠模型和现有的人类脑肿瘤数据库中获得的数据进行比较。将创建一个小鼠模型，其中 ERBB2 在小脑颗粒神经元中表达。在项目 4 中，S. Baker 正在研究 Pten 信号通路在大脑生长调节中的作用。这包括表征小脑下游效应基因的功能，以及创建新的突变小鼠品系以研究其对生长、增殖和肿瘤发生的贡献。