The DNA Damage Response and Tumorigenesis in the Brain

大脑中的 DNA 损伤反应和肿瘤发生

• 批准号: 9149701
• 负责人: PETER J MCKINNON
• 金额: $ 44.08万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9149701
• 关键词: Accounting; Address; B-Cell Lymphomas; Base Excision Repairs; Bioinformatics; Biology; Brain; Brain Neoplasms; Cell Proliferation; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Chromatin; Chromatin Structure; Chromosome Fragile Sites; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA Sequence Alteration; DNA strand break; Defect; Development; Disease; Epigenetic Process; Event; Gene Cluster; Gene Expression; Genome; Genome Stability; Genomic Instability; Glioblastoma; Glioma; Gliomagenesis; Heterogeneity; Histology; Histone H3; Histones; Histopathology; Human; Hypersensitivity; Individual; Laboratories; Lesion; Link; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Modeling; Molecular; Molecular Biology; Molecular Profiling; Mus; Mutation; Neoplasms; Nervous system structure; Nonhomologous DNA End Joining; PDGFRA gene; Pathogenesis; Pathway interactions; Patients; Population; Predisposition; Proteins; Proto-Oncogenes; Research; Series; Signal Transduction; Solid; Staging; Stress; Survival Rate; TP53 gene; Therapeutic; Topoisomerase; Tumor Biology; Tumor Suppression; base; cell type; childhood cancer mortality; genetic signature; genome integrity; homologous recombination; human disease; improved; in vivo; member; mouse model; mutant; nerve stem cell; neurodevelopment; neurogenesis; new therapeutic target; novel; outcome forecast; prevent; progenitor; programs; relating to nervous system; repaired; research study; response; spatiotemporal; stem; targeted treatment; telomere; tumor; tumor heterogeneity; tumorigenesis

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.

摘要-项目2 脑肿瘤是儿童期最常见的实体恶性肿瘤，并且是癌症相关疾病的主要原因。 儿童死亡。15-20%的儿童CNS肿瘤是高级别胶质瘤（HGG），患有这些肿瘤的个体 肿瘤的2年存活率为10- 30%。尽管广泛的研究，以分子基础， 尽管神经胶质瘤的发生率很高，但目前的治疗仍然无效，并且大多数患者死于其疾病。更 有效的治疗策略可能来自对胶质瘤发病机制的详细了解。我们 已开发出一系列独特的与人类疾病相关的新型HGG小鼠模型，其中包括 其特征在于反映DNA损伤反应中特定缺陷的一系列组织病理学。在 本提案的目的1，我们将确定基因组改变和基因表达谱， 这些神经胶质瘤，特别是在人类疾病和其他小鼠神经胶质瘤模型的背景下， 或在本计划的其他项目中开发。我们还将确定肿瘤的基础 通过确定这些神经胶质瘤的详细发育起源和这些模型的异质性， 不同神经祖细胞对转化的相对易感性。这些分析将阐明关键的 神经胶质瘤的发病机制方面，有一个明确的信息缺乏。最后我们将 还确定这些模型与人类儿科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 目的2：我们提出实验来确定哪些DNA修复途径对基因组稳定性至关重要， 不同的皮质祖细胞阶段以及这与染色质的联系。因为组蛋白突变和其他 表观遗传学改变最近被确定为儿童HGG的致病分子变化，我们 这项研究对于理解DNA损伤信号传导、表观遗传学 和肿瘤发生。在目标3中，我们将确定DNA断裂是否与早期复制的脆性位点有关 解释了神经胶质瘤形成的核心DNA结构改变。总的来说，这项研究的结果将 提供基本的新信息来描述胶质瘤生物学，这对于开发靶向药物非常重要 治疗这些疾病。