Normal and Neoplastic Growth in the Brain

描述（由申请人提供）：脑肿瘤是儿童中最常见的实体恶性肿瘤，在研究不足的患者人群中造成毁灭性的死亡率和发病率。该项目的目标是提高对儿童高级别胶质瘤和髓母细胞瘤的认识和治疗。在上一个资助期间，项目负责人共同开发了新型小鼠模型，为大脑中正常和致瘤生长提供了关键的生物学见解，使用这些模型进行新治疗药物的临床前测试，并将研究结果转化为临床试验。全基因组测序工作还为儿科高级别胶质瘤和髓母细胞瘤的基因组景观提供了前所未有的视角，包括新发现的复发性突变，其中一些影响了表观遗传调控。目前的提案建立在这些令人兴奋的发现的基础上，有四个高度互动的项目，计划最先进的方法来确定遗传和表观遗传改变驱动发育中大脑肿瘤发生的机制。一个行政核心，一个生物信息学核心和一个神经病理学核心为所有项目提供必要的支持。在项目1中，S Baker将研究神经发育，胶质瘤发生和表观遗传调控之间的联系，重点是在儿科高级别胶质瘤中发现的复发性组蛋白H3突变。在项目2中，P McKinnon将采用新的胶质瘤小鼠模型来确定神经祖细胞中DNA损伤反应，复制应激和肿瘤发生之间的关键联系。在项目3中，M. M.将扩大她在开发髓母细胞瘤第3组亚组小鼠模型方面的进展，以确定髓母细胞瘤肿瘤发生中表观遗传调控和MYC信号传导之间的联系，并确定靶向抑制第3组髓母细胞瘤的表观遗传修饰剂的小分子。在项目4中，R Gilbertson将在他成功定义和建模髓母细胞瘤亚型的基础上，确定特定突变在后脑发育和髓母细胞瘤中的作用，并在临床前模型中开发和测试亚型特异性疗法。

DESCRIPTION (provided by applicant): Brain tumors are the most common group of solid malignancies in children, causing devastating mortality and morbidity in an understudied patient population. The goal of this program project is to improve understanding and treatment of pediatric high-grade glioma and medulloblastoma. During the last funding period, Project Leaders worked together to develop novel mouse models that provided key biological insights into normal and tumorigenic growth in the brain, used these models for preclinical testing of new therapeutic agents, and translated research results into clinical trials. Whole genome sequencing efforts also provided an unprecedented view of the genomic landscape of pediatric high-grade glioma and medulloblastoma, including newly identified recurrent mutations, some of which impact epigenetic regulation. The current proposal builds on these exciting findings, with four highly interactive projects that plan state-of-the-art approaches to determine the mechanisms through which genetic and epigenetic alterations drive tumorigenesis in the developing brain. An Administrative Core, a Bioinformatics Core, and a Neuropathology Core provide essential support to all projects. In Project 1, S Baker will investigate connections between neural development, gliomagenesis and epigenetic regulation, with a focus on recurrent histone H3 mutations found in pediatric high-grade glioma. In Project 2, P McKinnon will employ new mouse models of glioma to define critical connections between the DNA damage response in neural progenitors, replication stress, and tumorigenesis. In Project 3, M Roussel will extend her progress in developing a mouse model for the Group 3 subgroup of medulloblastoma to determine the connections between epigenetic regulation and MYC signaling in medulloblastoma tumorigenesis, and to identify small molecules targeting epigenetic modifiers that inhibit Group 3 medulloblastoma. In Project 4, R Gilbertson will build upon his success in defining and modeling medulloblastoma subtypes to determine the role of specific mutations in hindbrain development and medulloblastoma, and to develop and test subtype-specific therapies in preclinical models.