Radiation and Oxidative Stress: Effects on Neurogenesis

项目摘要/摘要 在癌症治疗期间，大脑可能暴露在电离辐射中，而辐射剂量可以 能否安全使用取决于肿瘤周围正常组织的耐受性。颅骨 辐射会导致认知损伤，影响到对学习至关重要的海马体 和记忆。认知障碍的发病机制尚不清楚，但有建议认为 这种损伤与海马神经发生改变和/或神经元破坏之间的机制联系 功能。最近的研究表明，氧化应激等环境影响也参与其中，这表明 活性氧(ROS)可能是控制前体细胞存活的关键环境信号 和差异化。因此，氧化应激和氧化还原动态平衡的维持可能起着重要作用。 在辐射后神经发生改变和认知障碍中的作用。 超氧化物歧化酶(SOD)亚型减轻ROS的生理和病理效应。 虽然超氧化物歧化酶的具体作用还不完全清楚，但胞外亚型(EC-SOD，SOD3) 已被证明与与海马体相关的认知功能有关。选管会的更改- 超氧化物歧化酶表达损害学习，EC-SOD缺乏的动物海马神经发生减少 (即EC-SOD基因敲除(KO)小鼠)。此外，当EC-SOD KO小鼠暴露于中等剂量的x- 射线，神经发生的预期减少不会发生。因此，我们假设氧化还原的变化 在神经源性人群的辐射反应背景下，动态平衡可以产生有益的影响。至 了解这种保护效应是如何起作用的，以及它是否最终可以被用来影响潜在的不利影响 在辐射对患者的影响方面，我们需要解决与氧化还原动态平衡相关的问题 动物。在这方面被认为特别重要的问题包括确定：a)是否 EC-SOD缺乏症可开启或关闭以影响保护效果(目标1)；b)如果保护效果 随着不同程度的氧化损伤(即辐射剂量)而变化(目标2)；c)如果 照射后EC-SOD缺乏的后果(行为)(目标3)；d)是否介导了保护作用 由于内源性炎症细胞(小胶质细胞)数量增加(目标4)；以及e)如果 保护作用是由于部位特异性(神经元、内皮)或全身性EC-SOD缺乏(目标5)。至 针对我们的假设，我们已经开发出独特的动物模型，在这些模型中，我们可以选择性地调节 EC-SOD的时间表达。辐射影响的定量评估将包括量化 神经发生、行为表现和与学习和记忆相关的分子决定因素 即刻早期基因Arc)。对这些端点进行量化和相互关联能力将提供新的见解 关于放射性脑损伤，并可能最终有助于制定战略或方法 颅脑照射严重并发症的处理。

Project Summary/Abstract The brain can be exposed to ionizing irradiation during cancer treatment, and the radiation dose that can be administered safely is dictated by the tolerance of normal tissues surrounding the tumor. Cranial irradiation can induce cognitive impairments that involve the hippocampus, a structure critical for learning and memory. The pathogenesis of cognitive impairment is poorly understood, but there are suggestions of a mechanistic link between such injury and altered hippocampal neurogenesis and/or disruption of neuronal function. Recent studies show that environmental influences such as oxidative stress are involved, suggesting that reactive oxygen species (ROS) may be critical environmental cues for the control of precursor cell survival and differentiation. Thus, oxidative stress and the maintenance of redox homeostasis may play an important role in altered neurogenesis and cognitive impairment after irradiation. The superoxide dismutase (SOD) isoforms mitigate the physiological and pathological effects of ROS. While the specific roles of the SODs are not completely understood, the extracellular isoform (EC-SOD, SOD3) has been shown to be associated with cognitive functions associated with the hippocampus. Alterations in EC- SOD expression impair learning, and hippocampal neurogenesis is reduced in animals deficient in EC-SOD (i.e., EC-SOD knockout (KO) mice). Additionally, when EC-SOD KO mice are exposed to a modest dose of x- rays, an expected decrease in neurogenesis does not occur. Thus, we hypothesize that an alteration in redox homeostasis can have beneficial effects in the context of radiation response in neurogenic populations. To understand how this protective effect works, and if it can ultimately be used to influence potential adverse effects of irradiation in patients, we will need to address issues related to redox homeostasis in the intact animal. Those issues deemed particularly important in this context include the determination of: a) whether EC-SOD deficiency can be turned on or off to affect the protective effects (Aim 1); b) if the protective effect changes with different degrees of oxidative insult (i.e. radiation dose) (Aim 2); c) if there are functional consequences (behavior) of EC-SOD deficiency after irradiation (Aim 3); d) if the protective effect is mediated by the presence of increased numbers endogenous inflammatory cells (microglia) (Aim 4); and e) if the protective effect is due to site specific (neuronal, endothelial) or systemic deficiency of EC-SOD (Aim 5). To address our hypothesis we have developed unique animal models in which we can selectively regulate the temporal expression of EC-SOD. The quantitative assessment of radiation effects will include quantification of neurogenesis, behavioral performance and a molecular determinant associated with learning and memory (the immediate early gene Arc). The ability to quantify and inter-relate these endpoints will provide novel insight about radiation brain injury, and may ultimately contribute to the development of strategies or approaches for the management of a very serious complication of cranial irradiation.