The DNA Damage Response and Tumorigenesis in the Brain

摘要-项目2 脑瘤是儿童最常见的实体恶性肿瘤，也是与癌症相关的主要原因。 儿童死亡。15%-20%的儿童中枢神经系统肿瘤是高级别胶质瘤(HGG)，而患有这些肿瘤的人 肿瘤的两年存活率为10%-30%。尽管对分子基础进行了广泛的研究 胶质瘤，目前的治疗方法仍然无效，大多数患者死于他们的疾病。更多 有效的治疗策略可能来自于对胶质瘤发病机制的详细了解。我们 已经开发出一系列独特的与人类疾病相关的新HGG小鼠模型，这些模型是 以反映DNA损伤反应中的特定缺陷的一系列组织病理学为特征的。在……里面 这项提案的目标1，我们将确定作为基础的基因组改变和基因表达谱 这些胶质瘤，特别是在人类疾病和其他小鼠胶质瘤模型的背景下，要么建立了 或在该计划的其他项目中开发。我们还将确定肿瘤的基础 这些模型的异质性通过确定这些胶质瘤的详细发育来源和 不同神经前体细胞对转化的相对易感性。这些分析将阐明关键 关于胶质瘤发病机制的几个方面，目前尚缺乏明确的信息。最后，我们会 还要确定这些模型与在人类儿科HGG中发现的其他突变的协同性，包括 组蛋白H3突变，利用该计划内其他项目产生的新模型。在……里面 目的2我们建议进行实验以确定哪些dna修复途径对基因组的稳定性至关重要。 不同的皮质祖细胞阶段及其与染色质的关系。因为组蛋白突变和其他 表观遗传学改变最近被确认为导致儿童HGG的分子变化，我们的 这项研究对于理解DNA损伤信号、表观遗传学 和肿瘤的发生。在目标3中，我们将确定DNA断裂是否与早期复制的脆弱部位有关 解释了胶质瘤发生中心的DNA结构变化。总而言之，这项研究的发现将 为描绘胶质瘤生物学提供基本的新信息，这对开发靶向将是重要的 对这些疾病的治疗。

Summary - Project 2 Brain tumors are the most common solid malignancies of childhood and are a leading cause of cancer-related death in children. 15-20% of pediatric CNS tumors are high-grade gliomas (HGG), and individuals with these tumors have a 2-year survival rate of 10-30%. Despite extensive research into the molecular basis of gliomagenesis, current therapies remain ineffective, and the majority of patients die from their disease. More effective therapeutic strategies are likely to come from a detailed understanding of glioma pathogenesis. We have developed a unique series of new HGG mouse models, relevant to the human disease, which are characterized by a range of histopathology reflective of the specific defect in the DNA damage response. In Aim 1 of this proposal we will determine the genomic alterations and gene expression profiles that underpin these gliomas, particularly in the context of human disease and other mouse glioma models, either established or under development in other projects in this program. We will also determine the basis for tumor heterogeneity in these models by ascertaining the detailed developmental origins of these gliomas and the relative susceptibility of different neural progenitors to transformation. These analyses will illuminate critical aspects of the pathogenesis of gliomas for which there is a paucity of definitive information. Finally, we will also determine cooperativity in these models with other mutations found in human pediatric HGG, including histone H3 mutations, taking advantage of novel models generated by other projects within the program. In Aim 2 we propose experiments to establish which DNA repair pathways are critical for genome stability at different cortical progenitor stages and how this is linked to chromatin. Because histone mutations and other epigenetic alterations have recently been identified as causative molecular changes in pediatric HGG, our study will be of central importance for understanding connections between DNA damage signaling, epigenetics and tumorigenesis. In Aim 3 we will determine if DNA breaks associated with early replicating fragile sites account for DNA structural alterations central to gliomagenesis. Collectively, findings from this study will provide fundamental new information to delineate glioma biology that will be important for developing targeted therapy for these diseases.