GENE AND CYTOKINE EXPRESSION IN THE CNS RADIORESPONSE

描述：减轻或保护免受辐射诱导的能力 中枢神经系统损伤在肿瘤治疗中具有明显的优势。 然而，在这方面， 在合理制定这种干预策略之前， 首先，我们必须加强对 这一重要的正常组织的基本放射生物学。 的响应 CNS对其他类型损伤的影响涉及特异性细胞因子水平的提高， 其被认为介导内在恢复过程。 现在好了 确定电离辐射的生物效应不包括 不仅细胞死亡，而且许多基因的表达也发生了变化。 拟议的研究是基于这样的前提，即 中枢神经系统至少部分地由特定的 细胞因子：辐射诱导基因表达的产物。 最终 该项目的目的是开发操纵 辐射介导的体内细胞因子产生的变化，这将允许 为了研究诱导基因表达在 CNS的放射反应。 首先，有必要确定 受CNS照射影响的特定基因和细胞因子， 调查责任机制。 这些研究将在 主要使用大鼠星形胶质细胞的体外培养物。 基于此 信息，战略将制定操纵辐射引起的 细胞因子在体内模型中的表达--成年大鼠颈椎 线. 对于这些研究，将使用两种操作方法： 放射诱导的基因表达的药理学抑制和离体 基因治疗 这些研究的目的是为了验证假设， 诱导的基因表达，因此，特定的细胞因子发挥作用， 在中枢神经系统的放射反应中起重要作用。 拟议的研究 不仅应该提供对基础放射生物学的见解， 中枢神经系统，但也应该建议治疗策略，减少 放射线对这个重要的正常组织造成的损伤

DESCRIPTION: The ability to alleviate or protect against radiation-induced CNS injury would be of obvious advantage in cancer treatment. However, before the rational development of such interventional strategies can proceed, it will first be necessary to increase our understanding of the fundamental radiobiology of this critical normal tissue. The response of CNS to other types of injury involves enhanced levels of specific cytokines, which are thought to mediate intrinsic recovery processes. It is now well established that the biological effects of ionizing radiation includes not only cell death, but also changes in the expression of a number of genes. The proposed research is based on the premise that the radioresponse of the CNS is at least partially governed by the increased production of specific cytokines: the products of radiation-induced gene expression. The ultimate aim of this project is to develop approaches for manipulating the radiation-mediated changes in cytokine production in vivo, which will allow for investigations into the role of induced gene expression in the radioresponse of the CNS. First, it will be necessary to identify the specific genes and cytokines that are affected by CNS irradiation and investigate the mechanism(s) responsible. These studies will be performed primarily using in vitro cultures of rat astrocytes. Based on this information, strategies will be developed for manipulating radiation-induced cytokine expression in an in vivo model -- the adult rat cervical spinal cord. For these investigations two methods of manipulation will be used: pharmacological inhibition of radiation-induced gene expression and ex vivo gene therapy. The goal of these studies is to test the hypothesis that induced gene expression and, consequently, specific cytokines play a significant role in the radioresponse of the CNS. The proposed studies should not only provide insights into the fundamental radiobiology of the CNS, but should also suggest therapeutic strategies for reducing radiation-induced damage in this critical normal tissue.