GENE AND CYTOKINE EXPRESSION IN THE CNS RADIORESPONSE

CNS 放射反应中的基因和细胞因子表达

• 批准号: 2443311
• 负责人: Philip Tofilon
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443311
• 关键词: astrocytes; central nervous system; cytokine; enzyme activity; enzyme inhibitors; gel mobility shift assay; gene expression; gene therapy; genetic transcription; immunocytochemistry; in situ hybridization; interleukin 1; ionizing radiation; laboratory rat; messenger RNA; neurogenetics; neurotrophic factors; northern blottings; oligodendroglia; polymerase chain reaction; protein kinase C; protein tyrosine kinase; radiation genetics; spinal cord injury; tissue /cell culture; transforming growth factors

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.

描述：减轻或防止辐射引起的能力 中枢神经系统损伤在癌症治疗中具有明显的优势。 然而， 在合理制定此类干预策略之前 继续前进，我们首先需要加深对 这种关键正常组织的基础放射生物学。 的回应 中枢神经系统对其他类型的损伤涉及特定细胞因子水平的升高， 这被认为可以调节内在的恢复过程。 现在已经好了 确定电离辐射的生物效应不包括 不仅仅是细胞死亡，还包括一些基因表达的改变。 所提出的研究基于以下前提： 中枢神经系统至少部分受到特定物质产量增加的控制 细胞因子：辐射诱导基因表达的产物。 终极 该项目的目的是开发操纵方法 辐射介导的体内细胞因子产生的变化，这将允许 用于研究诱导基因表达在 中枢神经系统的放射反应。 首先，需要确定 受中枢神经系统辐射影响的特定基因和细胞因子 调查负责的机制。 这些研究将进行 主要使用大鼠星形胶质细胞的体外培养物。 基于此 信息，将制定操纵辐射引起的策略 体内模型——成年大鼠颈椎中的细胞因子表达 绳索。 对于这些调查，将使用两种操纵方法： 辐射诱导的基因表达和离体的药理抑制 基因疗法。 这些研究的目的是检验以下假设： 诱导基因表达，因此特定细胞因子发挥作用 在中枢神经系统的放射反应中发挥着重要作用。 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，但也应该建议减少的治疗策略 辐射对这一重要正常组织造成的损伤。