Normal and Neoplastic Growth Regulation in the Brain

该项目的目标是增加对发育中大脑正常和肿瘤生长的分子基础的理解。最终目的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，这些项目调查了不同信号通路在中枢神经系统和脑肿瘤生长中的作用，并得到了行政核心和生物信息学和微阵列核心的支持。在项目1中，T. Curran利用髓母细胞瘤小鼠模型研究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 核移植入卵母细胞后髓母细胞瘤的表观遗传学和遗传学改变。在项目2中，P. McKinnon研究了DNA损伤信号对髓母细胞瘤形成的贡献。该项目是基于一种新的模型的表征髓母细胞瘤小鼠缺乏DNA连接酶IV和p53。这项分析将涉及比较不同的髓母细胞瘤的基因表达微阵列谱的程序。在项目3中，R. Gilbertson正在研究ERBB 2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对人髓母细胞瘤细胞系进行表征。这些信息将与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。将创建小鼠模型，其中ERBB 2在小脑颗粒神经元中表达。在项目4中，S.贝克正在研究 Pten信号通路在脑生长调节中的作用。这包括表征小脑中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。

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.