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

描述(申请人提供)：脑、头和颈部肿瘤的成功治疗受到电离辐射对正常脑组织的潜在损害的限制。虽然早期症状是可以治疗的，但迟发性认知和运动功能障碍S不可逆转，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，是脑辐射损伤的一贯特征。此外，成功地应用皮质类固醇治疗急性和慢性症状意味着炎症相关事件在辐射诱导的损伤和/或脆弱性中的重要性。根据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是辐射暴露后脑部炎症的关键介质。许多系统的研究，包括我们自己对全脑的研究，认为COX-2通过产生PGE2作为IL-1b作用的下游中介。总之，这些发现表明，辐射损伤后的神经炎症依赖于IL-1b/COX-2途径的假设。此外，对这一途径的干扰可能会对正常组织辐射损伤提供保护。为了确定IL-1和COX在辐射暴露后早期和晚期脑组织反应中的作用，提出了三个特定的目标。目的1利用3个IL-1信号通路缺陷的基因敲除小鼠(IL-1R1、IL-1a和IL-1b为空)。目的2将通过研究体细胞马赛克小鼠的脑辐射反应来确认IL-1的作用，这些小鼠被设计成局部过表达IL-1b或IL-1ra。最终目的是利用药理学和基因缺失的方法来研究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导致早期和延迟效应的分子和细胞机制，并可能直接涉及到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.