GENE AND CYTOKINE EXPRESSION IN THE CNS RADIORESPONSE

合理制定预防或治疗策略 中枢神经系统（CNS）的辐射损伤将需要更多的 完全了解这个关键正常的基本放射生物学 组织.其他类型的中枢神经系统损伤后，急性细胞死亡， 活化的二次反应过程发生后数小时至数天， 初始损伤并促进病变发展。此外还有 修复/恢复过程的激活，包括诱导基因编码 产生多种保护性细胞因子。这项提议的工作假设是， 类似的机制也适用于辐射引起的中枢神经系统损伤。 拟议的研究将涉及修复/恢复机制的诱导， 导致损伤发展的次级过程的激活。 关于启动保护机制，重点将放在 转录因子NF-κ B。放射诱导的CNS中NF-κ B活化是 随后是一个不应期，在此期间， 转录因子的激活是显着的 降低该提案的目的之一是确定监管机制， 辐射诱导的NF-kB活化，并确定其在 CNS的放射反应。关于次级过程，目的是定义 照射后大鼠脊髓中氧化应激的发生率。到 阐明氧化应激在放射性中枢神经系统损伤中的重要性， 特定抗氧化剂对辐射诱发的脊髓病的影响将是 研究了最后，线粒体的功能和代谢将被 在原代细胞培养物和照射后的脊髓中进行了研究。 有待检验的假设是，线粒体损伤是 氧化应激，并有助于辐射损伤的发展。是 预期描绘有助于组织的继发性事件 损伤和内在保护机制将导致识别 过程受到操纵，从而提供了发展的基础 放射诱导的CNS毒性的治疗。

The rational development of strategies for preventing or treating radiation injury in the central nervous system (CNS) will require a more complete understanding of the fundamental radiobiology of this critical normal tissue. After other types of CNS injury acute cell death is followed by the activation of secondary reactive processes that occur hours to days after the initial damage and contribute to lesion development. In addition, there is the activation of repair/recovery processes involving the induction of genes coding for a variety of protective cytokines. The working hypothesis of this proposal is that a similar scheme applies to the CNS injury induced by radiation. Proposed studies will address the induction of repair/recovery mechanisms and the activation of secondary processes that contribute to injury development. Regarding the activation of protective mechanisms, the focus will be on the transcription factor NF-kB. Radiation-induced activation of NF-kB in the CNS is followed by a refractory period during which the susceptibility of this transcription factor to activation by subsequent irradiation is significantly reduced. An aim of this proposal is to define the mechanisms that regulate radiation-induced NF-kB activation and to determine its significance in the radioresponse of the CNS. Regarding secondary processes, an aim is to define the incidence of oxidative stress in the rat spinal cord after irradiation. To address the significance of oxidative stress in radiation CNS injury, the effects of specific anti-oxidants on radiation-induced myelopathy will be investigated. Finally, mitochondrial function and metabolism will be investigated in primary cell cultures and in the spinal cord after irradiation. The hypothesis to be tested is that mitochondrial damage serves as a source of oxidative stress and contributes to the development of radiation injury. It is anticipated that delineating the secondary events that contribute to tissue injury and the intrinsic protection mechanisms will lead to identification of processes subject to manipulation and thus provide the basis for developing therapies for radiation induced CNS toxicity.