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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072156-04
Application #
2895720
Study Section
Special Emphasis Panel (ZRG2-ET-1 (03))
Program Officer
Stone, Helen B
Project Start
1996-07-01
Project End
2000-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Rosenthal, Rosalind A; Fish, Brian; Hill, Richard P et al. (2011) Salen Mn complexes mitigate radiation injury in normal tissues. Anticancer Agents Med Chem 11:359-72
Raju, U; Gumin, G J; Tofilon, P J (2000) Radiation-induced transcription factor activation in the rat cerebral cortex. Int J Radiat Biol 76:1045-53
Tofilon, P J; Fike, J R (2000) The radioresponse of the central nervous system: a dynamic process. Radiat Res 153:357-70
Raju, U; Gumin, G J; Tofilon, P J (1999) NF kappa B activity and target gene expression in the rat brain after one and two exposures to ionizing radiation. Radiat Oncol Investig 7:145-52
Noel, F; Raju, U; Happel, E et al. (1999) X-irradiation-induced loss of O-2A progenitor cells in rat spinal cord is inhibited by implants of cells engineered to secrete glial growth factor 2. Neuroreport 10:535-40
Noel, F; Gumin, G J; Raju, U et al. (1998) Increased expression of prohormone convertase-2 in the irradiated rat brain. FASEB J 12:1725-30
Raju, U; Gumin, G J; Noel, F et al. (1998) IkappaBalpha degradation is not a requirement for the X-ray-induced activation of nuclear factor kappaB in normal rat astrocytes and human brain tumour cells. Int J Radiat Biol 74:617-24
Noel, F; Tofilon, P J (1998) Astrocytes protect against X-ray-induced neuronal toxicity in vitro. Neuroreport 9:1133-7
Hayakawa, K; Borchardt, P E; Sakuma, S et al. (1997) Microglial cytokine gene induction after irradiation is affected by morphologic differentiation. Radiat Med 15:405-10
Noel, F; Ijichi, A; Chen, J J et al. (1997) X-ray-mediated reduction in basic fibroblast growth factor expression in primary rat astrocyte cultures. Radiat Res 147:484-9

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