IR-INDUCED APOPTOSIS IN THE DEVELOPING NERVOUS SYSTEM

描述（改编自申请人摘要）：脑肿瘤是仅次于 白血病是最常见的儿科恶性肿瘤。但不同于 白血病，脑肿瘤缺乏有效的治疗方法。电离辐射 是治疗脑肿瘤的常用策略之一。而 辐射可以有效地杀死肿瘤，这是癌症的毁灭性后果。 这种方法是对正常组织的损害，导致严重的认知障碍， 损伤据估计，接受治疗的儿童中， 对脑肿瘤进行放射治疗会出现明显的认知缺陷。的 辐射对肿瘤和正常组织的破坏作用可能 涉及细胞凋亡。预防对正常组织的损伤以及 放射增敏肿瘤将具有显著的临床影响。两 方案将受益于对监管的全面理解， 在凋亡过程中起作用的成分。因此，详细的分子 对凋亡过程的理解将为我们提供机会， 治疗干预和这些过程的临床控制。研究 本提案中所描述的将阐明电离的关键组成部分， 辐射诱导的神经系统凋亡途径，从而促进 更深入地了解分子间的相互作用。而且这个 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， 新的基因表达是IR诱导的细胞凋亡所必需的， 神经系统PI将使用cDNA微阵列分析， 差异分析和蛋白质相互作用分析，以确定哪些基因 是出生后早期神经系统IR诱导损伤的原因。的PI 随后将集中分析这些基因， 在野生型小鼠中调节，但在小鼠中不调节，如Atm或p53-null， 缺陷IR诱导的神经细胞凋亡。使用各种体外和体内 方法，他们将确定这些IR诱导基因的贡献 神经系统中的细胞凋亡。识别和表征 参与细胞死亡的基因对于合理设计方法将是有价值的 在临床上操纵这些过程。此外，作为神经退行性疾病 疾病可能涉及类似的凋亡途径，这项研究的结果表明， 将有助于理解神经退行性疾病中的神经元死亡。

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.