Genomic Instability in Mouse Medulloblastoma

DMA修复是生物体生存和稳态的一个基本过程。的 发育中的神经系统特别容易受到DNA损伤的影响， DNA修复缺陷脑肿瘤是16岁以下儿童中最常见的实体恶性肿瘤， 占所有儿童癌症的20%。其中髓母细胞瘤最常见 恶性脑瘤在上一个资助周期中，我们产生了新的小鼠模型， 髓母细胞瘤是由DNA修复缺陷引起的。的分子和细胞遗传学分析。 髓母细胞瘤的遗传病变表现出显著的一致性，其中许多 也是人类疾病的特征。这些数据突出了小鼠模型的实用性， 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 这些研究旨在探讨DNA损伤反应作为髓母细胞瘤屏障的重要性 在Ptch 1+小鼠中的形成。我们还开发了额外的DNA修复缺陷小鼠， DNA链断裂修复途径，我们将利用它来产生新的脑肿瘤模型。这些新 肿瘤模型将是重要的，为进一步描绘定义分子事件发生在 神经系统的肿瘤发生。最后，我们将确定操纵DNA损伤的效用， 反应作为一种手段，以加强脑肿瘤治疗。这些实验将扩大我们的 了解遗传毒性应激反应和神经稳态，并将具有重要意义， 建立脑肿瘤的病因。此外，这项工作也将是重要的，为提供一个合理的 为设计治疗这些肿瘤的新治疗方法奠定了基础。成功 这些目标的实现，有赖于我们与其他成员的研究工作的结合 这个项目的。

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.