Genomic Instability in Mouse Medulloblastoma

小鼠髓母细胞瘤的基因组不稳定性

• 批准号: 8459548
• 负责人: PETER J MCKINNON
• 金额: $ 25.52万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459548
• 关键词: 16 year old; Address; Applications Grants; Brain; Brain Neoplasms; Cells; Cerebellum; Child; Clinic; Cytogenetic Analysis; Cytoplasmic Granules; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA strand break; Data; Effectiveness; Etiology; Event; Funding; Generations; Genetic; Genomic Instability; Genotoxic Stress; Goals; Grant; Homeostasis; Human; Lead; Lesion; Link; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Modality; Modeling; Molecular; Molecular Cytogenetics; Molecular Genetics; Mus; Mutation; Neoplasms; Nervous system structure; Neurons; Organism; Pathway interactions; Process; Radiation; Research; Signal Transduction; Solid; Stress; Testing; Therapeutic; Translating; Work; base; biological adaptation to stress; design; human disease; improved; inhibitor/antagonist; insight; medulloblastoma; member; mouse model; mutant; neurodevelopment; novel; novel therapeutic intervention; prevent; programs; relating to nervous system; repaired; research study; response; smoothened signaling pathway; spatiotemporal; tumor; tumorigenesis

DMA repair is a fundamental process central to the survival and homeostasis of an organism. The developing nervous system is particularly susceptible to DNA damage and brain tumors can result from defective DNA repair. Brain tumors are the most common solid malignancy in children under 16 years of age and constitute about 20% of all pediatric cancer. Of these, medulloblastoma is the most common malignant brain tumor. During the previous funding cycle we generated novel mouse models of medulloblastoma that resulted from defective DNA repair. Molecular and cytogenetic analyses of the medulloblastomas revealed a remarkable uniformity in the genetic lesions that are present, many of which are also features of the human disease. These data highlight the utility of the mouse models for understanding the molecular basis of human medulloblastoma. In the current application we will expand these studies to investigate the importance of the DNA damage response as a barrier to medulloblastoma formation in Ptch1*'~ mice. We have also developed additional DNA repair deficient mice that target specific DNA strand-break repair pathways, which we will utilize to generate novel brain tumor models. These new tumor models will be important for further delineating the defining molecular events that occur during tumorigenesis in the nervous system. Finally, we will determine the utility of manipulating the DNA damage response as a means to enhance brain tumor therapy. Together, these experiments will expand our understanding of genotoxic stress responses and neural homeostasis, and will have significance for establishing the etiology of brain tumors. Furthermore, this work will also be important for providing a rational basis for designing novel therapeutic approaches for the treatment of these tumors. The successful completion of these goals will result from integration of our research efforts with those of the other members of this program.

DMA 修复是生物体生存和稳态的一个基本过程。这 发育中的神经系统特别容易受到 DNA 损伤，脑肿瘤可能由以下原因引起： 有缺陷的 DNA 修复。脑肿瘤是 16 岁以下儿童中最常见的实体恶性肿瘤 年龄，约占所有儿童癌症的 20%。其中，髓母细胞瘤是最常见的 恶性脑肿瘤。在上一个资助周期中，我们生成了新型小鼠模型 DNA 修复缺陷导致的髓母细胞瘤。分子和细胞遗传学分析 髓母细胞瘤揭示了存在的遗传病变的显着一致性，其中许多 也是人类疾病的特征。这些数据突出了鼠标模型的实用性 了解人类髓母细胞瘤的分子基础。在当前的应用程序中我们将扩展 这些研究旨在调查 DNA 损伤反应作为髓母细胞瘤屏障的重要性 Ptch1*'~ 小鼠中的形成。我们还开发了额外的 DNA 修复缺陷小鼠，针对特定的 DNA 链断裂修复途径，我们将利用它来生成新型脑肿瘤模型。这些新 肿瘤模型对于进一步描述发生在肿瘤发生过程中的定义性分子事件非常重要。 神经系统的肿瘤发生。最后，我们将确定操纵 DNA 损伤的效用 反应作为增强脑肿瘤治疗的一种手段。总之，这些实验将扩展我们的 了解基因毒性应激反应和神经稳态，将对 建立脑肿瘤的病因学。此外，这项工作对于提供合理的 为设计治疗这些肿瘤的新治疗方法奠定了基础。成功者 这些目标的完成将通过我们与其他成员的研究工作的整合来实现 这个程序的。