Radiation and Oxidative Stress: Effects on Neurogenesis

描述（由申请人提供）：在癌症治疗期间，大脑可能暴露于电离辐射，并且可以安全施用的辐射剂量取决于肿瘤周围正常组织的耐受性。脑照射可引起涉及海马体的认知障碍，海马体是学习和记忆的关键结构。认知障碍的发病机制知之甚少，但有建议的机制之间的联系，这种损伤和海马神经发生和/或神经元功能的破坏改变。最近的研究表明，环境的影响，如氧化应激参与，表明活性氧（ROS）可能是关键的环境线索的前体细胞的生存和分化的控制。因此，氧化应激和氧化还原稳态的维持可能在辐射后改变的神经发生和认知障碍中起重要作用。超氧化物歧化酶（SOD）亚型减轻ROS的生理和病理作用。虽然SOD的具体作用尚未完全了解，但细胞外同工型（EC-SOD，SOD 3）已显示与海马相关的认知功能相关。EC-SOD表达的改变损害学习，并且在缺乏EC-SOD的动物中海马神经发生减少（即，EC-SOD敲除（KO）小鼠）。此外，当EC-SOD KO小鼠暴露于中等剂量的X射线时，不会发生预期的神经发生减少。因此，我们假设，在神经源性人群的辐射反应的背景下，氧化还原稳态的改变可以有有益的影响。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患者辐射的潜在不良反应，我们将需要解决与完整动物中氧化还原稳态相关的问题。在此背景下被认为特别重要的那些问题包括确定：a）EC-SOD缺陷是否可以开启或关闭以影响保护作用（目标1）; B）保护作用是否随不同程度的氧化损伤而改变（即辐射剂量）（目标2）; c）如果有功能性后果照射后EC-SOD缺乏的（行为）（目的3）; d）保护作用是否由内源性炎症细胞数量增加介导（小胶质细胞）（目的4）;和e）如果保护作用是由于EC-SOD的位点特异性（神经元、内皮）或全身性缺陷（目的5）。为了解决我们的假设，我们已经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。辐射影响的定量评估将包括神经发生、行为表现和与学习和记忆有关的分子决定因素（即早期基因Arc）的定量。量化这些终点并将其相互关联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用于管理非常严重的颅脑照射并发症的策略或方法。 公共卫生相关性：癌症治疗期间大脑的辐射暴露可诱发认知障碍，并且通常涉及氧化应激等环境影响。正常脑组织中抗氧化分子的操纵可能会影响与行为表现相关的关键事件。在缺乏特定抗氧化基因的动物中，量化和相互关联的神经发生、神经元活性和行为表现的测量的能力将提供关于放射性脑损伤的新见解，并且可能最终有助于开发用于管理非常严重的颅脑照射并发症的策略或方法。

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.