Neuroinflammation in CNS Radiation Injury: IL-1 & COX-2

描述（由申请人提供）：成功管理脑，头部和颈部肿瘤受到电离辐射对正常脑组织的潜在损伤的限制。虽然早期症状是可以治疗的，但认知和运动功能障碍的延迟发作是不可逆转的，并导致发病率和死亡率。神经炎性改变，包括神经胶质细胞的激活、细胞因子和其他促炎介质的表达，是脑辐照损伤的一致特征。此外，皮质类固醇治疗急性和慢性症状的成功应用意味着炎症相关事件在辐射引起的损伤和/或易损性中的重要性。基于IL-1b和COX-2在神经炎症和脑损伤中的关键作用，以及本提案中详细介绍的初步研究，我们假设IL-1b和COX-2是辐射暴露后脑炎症的关键介质。许多系统的研究，包括我们自己在全脑中的研究，都表明COX-2通过PGE2的产生，作为IL-1b作用的下游介质。总之，这些发现提出了辐射损伤后神经炎症依赖于IL-1b/COX-2途径的假设。此外，干扰这一途径可能对正常组织辐射损伤具有保护作用。我们提出了三个具体目标来确定IL-1和COX在辐射暴露后早期和晚期脑组织反应中的作用。Aim 1利用3系IL-1信号通路缺陷的敲除小鼠（IL-1R1、IL-1a和IL-1b无效）。目的2将通过研究经局部过表达IL-1b或IL-1Ra的体细胞镶嵌小鼠的脑辐照反应来证实IL-1的作用。最终目的是利用药理学和基因删除方法来研究COX-2在中枢神经系统辐射反应中的具体作用。这项工作将有助于更好地了解早期和延迟效应的分子和细胞机制，并可能直接影响预防和治疗脑辐射损伤的特定靶点。

DESCRIPTION (provided by applicant): Successful management of tumors in the brain, head and neck is limited by potential damage to normal brain tissue caused by ionizing radiation. Although early symptoms are treatable, the delayed onset of cognitive and motor dysfunction s irreversible and contributes to morbidity and mortality. Neuroinflammatory changes, including activation of glial cells and expression of cytokines and other proinflammatory mediators, are a consistent feature of brain irradiation injury. Moreover, successful administration of corticosteroids for treatment of acute and chronic symptoms implicates the importance of inflammation-related events in radiation-induced injury and/or vulnerability. Based on their key roles in neuroinflammation and brain injury, and preliminary studies detailed in this proposal, we hypothesize that IL-1b and COX-2 are critical mediators of brain inflammation following radiation exposure. Studies in numerous systems, including our own investigations in whole brain, place COX-2, working through production of PGE2, as a downstream mediator of IL-1b action. Together, these findings suggest the hypothesis that neuroinflammation following radiation injury is dependent on an IL-1b/COX-2 pathway. Moreover, interference with this path may confer protection to normal tissue radiation injury. Three specific aims are proposed to establish the roles of IL-1 and COX in early and late brain tissue reaction following radiation exposure. Aim 1 utilizes 3 lines of knockout mice with defective IL-1 signaling pathways (null for IL-1R1, IL-1a, and IL-1b). Aim 2 will confirm the role of IL-1 by investigating brain irradiation responses in somatic mosaic mice engineered to regionally overexpress IL-1b or IL-1Ra. The final aim utilizes pharmacological and gene deletion approaches to investigate the specific role of COX-2 in CNS radiation responses. This work will provide a better understanding of the molecular and cellular mechanisms contributing to early and delayed effects, and may directly implicate specific targets for prevention and treatment of brain radiation injury.