Genomic Instability in Mouse Medulloblastoma

小鼠髓母细胞瘤的基因组不稳定性

• 批准号: 7647492
• 负责人: PETER J MCKINNON
• 金额: $ 30.96万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647492
• 关键词: 16 year old; Address; Applications Grants; Brain; Brain Neoplasms; Cells; Cerebellum; Child; Clinic; Cytogenetic Analysis; Cytoplasmic Granules; DNA Damage; DNA Repair; DNA Repair Pathway; DNA strand break; Data; Effectiveness; Erinaceidae; 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; 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修复是生物生存和稳态核心的基本过程。这 发展神经系统特别容易受到DNA损伤的影响，脑肿瘤可能是由 DNA修复有缺陷。脑肿瘤是16岁以下儿童中最常见的固体恶性肿瘤 年龄，约占所有小儿癌的20％。其中，髓母细胞瘤是最常见的 恶性脑肿瘤。在先前的资金周期中，我们生成了新颖的鼠标模型 髓母细胞瘤是由DNA修复缺陷引起的。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统一性，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 这些研究是为了研究DNA损伤反应作为髓母细胞瘤的障碍的重要性 PTCH1*'〜小鼠中的形成。我们还开发了靶向特定的其他DNA修复缺陷的小鼠 DNA链破裂的修复途径，我们将利用该途径产生新型的脑肿瘤模型。这些新 肿瘤模型对于进一步描述在 神经系统中的肿瘤发生。最后，我们将确定操纵DNA损伤的实用性 反应是增强脑肿瘤疗法的一种手段。这些实验将加在一起扩大我们的 了解遗传毒性应激反应和神经稳态，并将 建立脑肿瘤的病因。此外，这项工作对于提供理性也很重要 设计新的治疗方法来治疗这些肿瘤的基础。成功 这些目标的完成将是由我们与其他成员的研究工作整合在一起的 这个程序。