Normal & Neoplastic Growth in the Brain

描述（由项目负责人提供）：脑肿瘤是儿童中最常见的实体恶性肿瘤，在一个研究非常不足的患者群体中造成毁灭性的死亡率和发病率。这个项目的目标是提高对儿童脑肿瘤的理解和治疗。在第一个资助期内，项目负责人合作开发了新的小鼠模型，为小脑生长调节和成神经管细胞瘤的发展提供了关键的生物学见解，并将这些模型用于新治疗药物的相关临床前测试，并将研究结果转化为临床试验。目前的应用程序扩展了该计划的重点，以涵盖额外的儿科脑肿瘤。五个互动项目计划利用人类肿瘤和小鼠模型来研究儿童脑肿瘤和大脑发育背景下的信号转导、基因表达和功能，指导大脑生长调节的研究。行政核心，生物信息学和生物技术核心和神经病理学核心为所有项目提供必要的支持。在Project 1中，S. Baker利用她开发的大量原发肿瘤和新型胶质瘤小鼠模型，研究了儿童高级胶质瘤的分子发病机制。在项目2中，T. Curran研究了Hedgehog信号小分子抑制剂的作用机制，他在他的模型系统中展示了切除的髓母细胞瘤。在Project 3中，R. Gilbertson将通过对人类肿瘤的分析和小鼠模型的开发来定义成神经管细胞瘤的分子亚群，并将表征成神经管细胞瘤亚群中的癌症干细胞及其生态位。在项目4中，P. McKinnon将进一步分析脑肿瘤发展背后的缺陷DNA损伤反应，并将确定DNA修复抑制剂作为脑肿瘤治疗方法的效果。在Project 5中，M. Roussel和C. Sherr将探索成神经管细胞瘤的致癌转化机制，并将定义在小脑发育和成神经管细胞瘤中调节基因表达的microrna。小组内的综合分析将确定儿童脑肿瘤发生中常见和独特的信号转导途径。

DESCRIPTION (provided by Project Leader): Brain tumors are the most common group of solid malignancies in children, causing devastating mortality and morbidity in a very understudied patient population. The goal of this program project is to improve understanding and treatment of pediatric brain tumors. During the first funding period, Project leaders worked together to develop novel mouse models that provided key biological insights into cerebellar growth regulation and medulloblastoma development, used these models for relevant preclinical testing of new therapeutic agents, and translated research results into clinical trials. The current application expands the focus of the program to encompass additional pediatric brain tumors. Five interactive projects plan directed studies of growth regulation in the brain using human tumors and mouse models to study signal transduction, gene expression and function in the context of pediatric brain tumors and brain development. An Administrative Core, a Bioinformatics and Biotechnology Core and a Neuropathology Core provide essential support to all projects. In Project 1, S. Baker investigates the molecular pathogenesis of pediatric high-grade glioma taking advantage of a large collection of primary tumors and novel mouse models for glioma that she developed. In Project 2, T. Curran investigates the mechanism of action of a small molecule inhibitor of Hedgehog signaling that he showed ablated medulloblastoma in his model systems. In Project 3, R. Gilbertson will define molecular subgroups of medulloblastoma through analysis of human tumors and development of mouse models, and will characterize cancer stem cells and their niches in subclasses of medulloblastoma. In Project 4, P. McKinnon will further his analysis of defective DNA damage response underlying brain tumor development and will determine the effects of DNA repair inhibitors as a therapeutic approach for brain tumors. In Project 5, M. Roussel and C. Sherr will explore mechanisms of oncogenic transformation in medulloblastoma, and will define microRNAs that modulate gene expression in cerebellar development and medulloblastoma. Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis.