NORMAL & NEOPLASTIC GROWTH IN THE BRAIN

总体方案摘要 脑肿瘤是最常见的小儿实体恶性肿瘤，也是癌症相关死亡的主要原因 小儿本项目的长期目标是提高对弥漫性脑血管病的认识和治疗。 脑桥内神经胶质瘤（DIPG）和髓母细胞瘤（MB），这两种肿瘤在脑内引起毁灭性的死亡率和发病率， 孩子在上一个资助期内，P01研究人员Baker，Mrsel和Gilbertson证明了重要的 DIPG和MB中表观遗传失调的作用，儿童脑肿瘤突变在应激中的作用 反应和MB亚型的治疗脆弱性。P01研究员Northcott作为一个新项目加入 领导人提出了一项基于发现一种新的MB癌症易感基因的建议。这个高度互动 研究小组提出了一系列综合实验，以利用最近的进展和最先进的 研究异常细胞命运/细胞状态调节的技术，以确定表观基因组的贡献， 转录组和蛋白质组失调破坏发育和肿瘤发生，并确定 儿童后脑发育和表观遗传功能依赖性和测试治疗弱点 肿瘤的在项目1中，S Baker专注于H3 K27 M突变在发育中断中的作用， 肿瘤发生的肿瘤启动和时空选择性，以及ACVR 1如何协同作用 和PI 3 K/mTOR途径影响对选择性抑制剂的治疗反应的异质性。在项目2中， Macksel研究了甲基转移酶SMYD 3的作用，并测试了增强甲基转移酶SMYD 3的药物组合。 甲基转移酶抑制剂在第3组MB亚型中的疗效。在项目3中，P Northcott评估了 ELP 1的功能驱动MB易感性，干扰翻译延伸的调节，并与 SHH-MB亚型中的其他突变。在项目4中，R Gilbertson研究了DDX 3X突变如何破坏 细胞命运决定，转录和翻译调控，并研究新的疗法，以利用 WNT-MB血脑屏障缺陷。所有四个项目都依赖于核心B的杰出专业知识， 将分析下一代序列数据，包括来自多个基因组的数据的综合交叉比较。 将采用严格的生物统计方法进行实验设计和解释。核心 C是所有项目不可或缺的，并将提供所有肿瘤模型研究的专家神经病理学审查， 评估其与原发性人类疾病的相似性和相关性的计划， 分析和优化免疫组织化学分析。该计划的集体努力将影响我们的 了解DIPG和MB的疾病发病机制，超越儿科后脑肿瘤，以增强 了解表观基因组，转录组和蛋白质组的异常调节如何破坏正常的 发展和促进癌症。我们的成功是由我们强大的生产记录保证的。 合作，独特的资源和优秀的核心，以促进收购，交流， 数据整合。

Overall Program Summary Brain tumors are the most common pediatric solid malignancies, and the leading cause of cancer-related death in children. The long-term goal of this Program Project is to improve understanding and treatment of diffuse intrinsic pontine glioma (DIPG) and medulloblastoma (MB), which cause devastating mortality and morbidity in children. Over the last funding period, P01 investigators Baker, Roussel and Gilbertson demonstrated important contributions of epigenetic dysregulation in DIPG and MB, a role for pediatric brain tumor mutations in stress response, and therapeutic vulnerabilities in MB subtypes. P01 Investigator Northcott joins as a new Project leader with a proposal based on the discovery of a new MB cancer predisposition gene. This highly interactive team proposes an integrated series of experiments to leverage recent progress and the most advanced techniques to investigate aberrant cell fate/cell state regulation, to determine the contribution of epigenome, transcriptome and proteome dysregulation to disrupted development and tumorigenesis, and to identify developmental and epigenetic functional dependencies and test therapeutic vulnerabilities of pediatric hindbrain tumors. In Project 1, S Baker is focused on the contribution of H3K27M mutations in disrupted development, tumor initiation and spatiotemporal selectivity of tumorigenesis, and how cooperative contributions of ACVR1 and PI3K/mTOR pathways influence heterogeneity of therapeutic response to selective inhibitors. In Project 2, M Roussel investigates the role of the methyltransferase SMYD3, and tests drug combinations that enhance efficacy of methyltransferase inhibitors in the Group 3 MB subtype. In Project 3, P Northcott evaluates how loss of function in ELP1 drives MB predisposition, perturbs regulation of translation elongation, and cooperates with other mutations in the SHH-MB subtype. In Project 4, R Gilbertson investigates how DDX3X mutations disrupt cell fate decisions, transcription and translation regulation, and investigates novel therapies to exploit the defective blood-brain-barrier in WNT-MB. All four projects rely on the outstanding expertise in Core B, where all next-generation sequence data will be analyzed including integrated cross-comparison of data from multiple projects, and rigorous biostatistical approaches will be applied for experimental design and interpretation. Core C is integral to all projects and will provide expert neuropathological review of all tumor models studied in the program to assess their similarity and relevance to primary human disease and will assist with phenotype analyses and optimizing immunohistochemical analyses. The collective efforts of the Program will impact our understanding of disease pathogenesis of DIPG and MB, extend beyond pediatric hindbrain tumors, to enhance understanding of how aberrant regulation of the epigenome, transcriptome and proteome disrupt normal development and contribute to cancer. Our success is guaranteed by our strong track record of productive collaborations, the unique resources and the outstanding Cores to facilitate the acquisition, exchange, and integration of data.