Radiation and Oxidative Stress: Effects on Neurogenesis

描述（由申请人提供）：在癌症治疗期间，大脑可能会暴露在电离辐射下，可以安全给予的辐射剂量取决于肿瘤周围正常组织的耐受性。颅脑照射可诱发认知障碍，涉及海马体，一个对学习和记忆至关重要的结构。认知障碍的发病机制尚不清楚，但这种损伤与海马神经发生改变和/或神经元功能破坏之间存在机制联系。最近的研究表明，环境影响如氧化应激参与其中，表明活性氧（ROS）可能是控制前体细胞存活和分化的关键环境信号。因此，氧化应激和氧化还原稳态的维持可能在辐照后神经发生改变和认知障碍中起重要作用。超氧化物歧化酶（SOD）异构体减轻ROS的生理和病理作用。虽然sod的具体作用尚不完全清楚，但细胞外异构体（EC-SOD, SOD3）已被证明与海马相关的认知功能有关。EC-SOD表达的改变会损害学习能力，在EC-SOD缺乏的动物（即EC-SOD敲除（KO）小鼠）中，海马神经发生减少。此外，当EC-SOD KO小鼠暴露于适度剂量的x射线时，预期的神经发生减少并未发生。因此，我们假设氧化还原稳态的改变对神经源性人群的辐射反应有有益的影响。为了了解这种保护作用是如何起作用的，以及它是否最终可以用于影响照射对患者的潜在不良影响，我们需要解决与完整动物的氧化还原稳态相关的问题。在这方面被认为特别重要的问题包括确定：a) EC-SOD缺乏是否可以开启或关闭以影响保护作用（目标1）；b)如果保护作用随氧化损伤程度（即辐射剂量）的不同而变化（目标2）；c)辐照后EC-SOD缺乏是否有功能后果（行为）（目标3）；d)如果这种保护作用是由内源性炎症细胞（小胶质细胞）数量增加介导的（Aim 4）；e)如果保护作用是由于部位特异性（神经元，内皮细胞）或全身EC-SOD缺乏（Aim 5）。为了解决我们的假设，我们开发了独特的动物模型，我们可以选择性地调节EC-SOD的时间表达。辐射效应的定量评估将包括神经发生、行为表现和与学习和记忆相关的分子决定因素（即早期基因弧）的定量评估。量化和相互关联这些终点的能力将为放射性脑损伤提供新的见解，并可能最终有助于制定策略或方法来管理颅脑辐照的严重并发症。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Radiation exposure of the brain during cancer treatment can induce cognitive impairments, and often involves environmental influences such as oxidative stress. The manipulation of anti-oxidant molecules in normal brain tissues may impact critical events associated with behavioral performance. The ability to quantify and inter-relate measures of neurogenesis, neuronal activity and behavioral performance in animals deficient in a specific anti-oxidant gene 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.