Genomic Instability in Mouse Medulloblastoma

DNA修复是生物体生存和动态平衡的一个基本过程。这个 发育中的神经系统特别容易受到DNA损伤，脑肿瘤可能由 DNA修复有缺陷。脑瘤是16岁以下儿童最常见的实体恶性肿瘤 年龄，约占所有儿科癌症的20%。其中，髓母细胞瘤最为常见。 恶性脑瘤。在上一个资金周期中，我们生成了新的鼠标模型 由于DNA修复缺陷而导致的髓母细胞瘤。黑色素瘤细胞的分子遗传学分析 髓母细胞瘤显示了存在的遗传损害的显著一致性，其中许多 也是人类疾病的特征。这些数据突出显示了鼠标型号在 了解人类髓母细胞瘤的分子基础。在当前应用程序中，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ptch1*‘~小鼠体内形成。我们还培育了另一种针对特定基因的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瘤模型。这些新的 肿瘤模型将是重要的，以进一步描述发生在 神经系统中的肿瘤发生。最后，我们将确定操纵DNA损伤的效用 作为提高脑肿瘤治疗效果的一种手段。总之，这些实验将扩大我们的 了解遗传毒性应激反应和神经动态平衡，对 建立脑肿瘤的病因学。此外，这项工作也将对提供一个合理的 为设计治疗这些肿瘤的新的治疗方法奠定了基础。成功者 完成这些目标将是我们的研究努力与其他成员的努力相结合的结果 这个节目的一部分。

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.