IR-INDUCED APOPTOSIS IN THE DEVELOPING NERVOUS SYSTEM

描述(摘自申请者的摘要)：脑瘤仅次于 白血病是最常见的儿科恶性肿瘤。然而，不同于 对于白血病，脑肿瘤缺乏有效的治疗方法。电离辐射 是治疗脑肿瘤最常用的策略之一。而当 辐射可以有效地杀死肿瘤，这是一种毁灭性的后果 这种方法是对正常组织的损害，导致严重的认知 减损。据估计，超过60%的儿童接受了治疗 对于受辐射的脑肿瘤，会发展成严重的认知缺陷。这个 辐射对肿瘤和正常组织的破坏性影响可能会 涉及到细胞凋亡。预防对正常组织的损害以及 肿瘤的放射增敏将产生重大的临床影响。两者都有 方案将受益于全面了解法规 在细胞凋亡过程中运行的组件。因此，一个详细的分子 对细胞凋亡过程的了解将为 这些过程的治疗干预和临床控制。研究 将阐明电离的关键组件 辐射诱导神经系统中的凋亡途径，从而促进 对所涉及的分子相互作用有更深入的了解。此外，这一点 研究还将提供有关死亡作用的基本信息 神经系统中的调节器。调查人员的初步数据显示， 发育中IR诱导的细胞凋亡需要新的基因表达 神经系统。PI将使用cDNA微阵列分析，具有代表性 差异分析和蛋白质相互作用分析确定哪些基因 是IR引起的出生后早期神经系统损伤的原因。《少年派》 随后将通过选择那些 在野生型小鼠中受调控，但在ATM或p53-空等小鼠中不受调控，具有 缺陷性IR诱导神经细胞凋亡。使用各种体外和体内实验 方法，他们将确定这些IR诱导基因的贡献 导致神经系统中的细胞凋亡。识别和表征 参与细胞死亡的基因将对合理设计治疗方法很有价值 在临床上操纵这些过程。此外，作为神经退行性疾病 疾病可能采用类似的细胞凋亡途径，这一提议的发现 对于理解神经退行性疾病中的神经元死亡将是相关的。

DESCRIPTION (adapted from applicant's abstract): Brain tumors are second only to leukemia as the most prevalent form of pediatric malignancy. However, unlike leukemia, effective treatments for brain tumors are lacking. Ionizing radiation is one of the more common strategies used to treat brain tumors. While radiation can be effective in killing the tumor, a devastating consequence of this approach is damage to normal tissues, resulting in severe cognitive impairment. It has been estimated that upward of 60 percent of children treated for brain tumors by irradiation develop significant cognitive defects. The damaging effects of radiation upon both tumor and normal tissue are likely to involve apoptosis. The prevention of damage to normal tissue as well as radiosensitizing the tumor would have significant clinical impact. Both scenarios would benefit from a comprehensive understanding of the regulatory components operating during apoptosis. Therefore, a detailed molecular understanding of the apoptotic process will afford the opportunity for therapeutic intervention and the clinical control of these processes. Research described in this proposal will elucidate critical components of the ionizing radiation induced apoptotic pathway in the nervous system, thereby facilitating a greater understanding of the molecular interplay involved. Additionally, this research will also provide fundamental information about the role of death regulators in the nervous system. The investigator's preliminary data show that new gene expression is required for IR-induced apoptosis in the developing nervous system. The PI will use cDNA microarray analysis, representational difference analysis and protein interaction analysis to determine which genes are causal in IR-induced damage of the early postnatal nervous system. The PI will subsequently focus the analysis of these genes by selecting those that are regulated in wildtype mice, but not in mice such as Atm or p53-null, with defective IR-induced neural apoptosis. Using a variety of in vitro and in vivo approaches, they will determine the contribution of these IR-induced genes towards apoptosis in the nervous system. Identifying and characterizing the genes involved in cell death will be valuable for rational design of approaches to manipulate these processes clinically. Moreover, as neurodegenerative disease may engage similar apoptotic pathways, the findings from this proposal will be relevant for understanding neuronal death in neurodegenerative disease.