Normal and Neoplastic Growth Regulation in the Brain

描述(由申请者提供)：本申请代表对补充资金的申请，以支持在现有计划项目中增加新项目。项目5涉及细胞周期调节因子在颗粒神经元增殖和髓母细胞瘤细胞中的作用，该研究来自Martine F.Roussel博士和Charles L Sherr博士。最初的计划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了解。最终目的是利用这一知识设计治疗髓母细胞瘤的新策略，髓母细胞瘤是最常见的儿童中枢神经系统恶性肿瘤。这一目标是通过四个互动项目来实现的，这些项目调查不同信号通路在中枢神经系统和脑肿瘤生长中的作用，并由行政核心和生物信息学和 微阵列核心。在项目1中，T.Curran利用髓母细胞瘤的小鼠模型来研究Shh/PTC/Smo通路在肿瘤发生中的作用。这包括在细胞培养和活体中使用药物抑制剂，Glil的分子特征，以及通过将核移植到卵母细胞中来比较髓母细胞瘤的表观遗传学和遗传学改变。在项目2中，P·麦金农研究了DNA损伤信号在髓母细胞瘤形成中的作用。这个项目是基于一种新的小鼠髓母细胞瘤模型的特征，该模型缺乏DNA连接酶IV和p53。这项分析将包括比较项目中不同髓母细胞瘤的基因表达微阵列图谱。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对人髓母细胞瘤细胞系进行表征。这些信息将与在小鼠模型和现有的人脑肿瘤数据库中获得的数据进行比较。将建立ERBB2在小脑颗粒神经元中表达的小鼠模型。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，以及创造新的突变小鼠品系，以调查其对生长、增殖和肿瘤形成的贡献。

DESCRIPTION (provided by applicant): This application represents a request for supplemental funds to support the addition of a new project to an existing program project. Project 5 concerns the role of cell cycle regulators in granule neuron proliferation and in medulloblastoma cells from Drs. Martine F. Roussel and Charles L Sherr. The goal of the original 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 at the Shh/Ptc/Smo pathway in tumorigenesis. This involves the use of pharmacological inhibitors in cell culture and in viva, a molecular characterization of Glil 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 medulloblastomas 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 i 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 an, tumorigenesis.