Normal and Neoplastic Growth in the Brain

描述(由申请人提供)：脑瘤是儿童中最常见的实体恶性肿瘤，在研究不足的患者群体中造成毁灭性的死亡和发病率。该计划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。在上一次资助期间，项目负责人共同开发了新的小鼠模型，提供了对大脑正常和致瘤生长的关键生物学见解，将这些模型用于新治疗剂的临床前测试，并将研究结果转化为临床试验。全基因组测序工作也为儿童高级别胶质瘤和髓母细胞瘤的基因组图景提供了前所未有的视角，包括新发现的反复突变，其中一些影响表观遗传调控。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，这些项目计划采用最先进的方法来确定基因和表观遗传变化推动发育中大脑肿瘤发生的机制。行政核心、生物信息学核心和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·贝克将研究神经发育、胶质瘤发生和表观遗传调控之间的联系，重点是在儿童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将使用新的胶质瘤小鼠模型来确定神经前体细胞的DNA损伤反应、复制压力和肿瘤发生之间的关键联系。在项目3中，M Roussel将扩展她为髓母细胞瘤第三组亚组开发小鼠模型的进展，以确定表观遗传调控和MYC信号在髓母细胞瘤发生中的联系，并识别针对抑制第三组髓母细胞瘤的表观遗传修饰物的小分子。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治疗。

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.