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.
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