The gliomas, tumors arising from the glial cells on the nervous system, are a common and discouraging problem in clinical oncology; prospects for improving treatment results must be based on a better understanding of the biology of these neoplasms. While little is now known about the genetic basis of glial tumorgenesis, research approaches based on tumor tissue suffer serious limitations. The development and application o two model systems to overcome this problem is proposed here: I. An in vitro model system: I suggest that the cells in primary rodent brain cultures that display mature glial features are suitable models for the cells of origin of some human gliomas. I will characterize the response of these model cells to several genetic changes that have been implicated in human glial neoplasia. I will engineer the expression of a number of growth control-related genes (oncogenes and genes encoding growth factors) in model glial cells. After transfer of these exogenous genes, transformation-related parameters for cells in culture, and also alteration of differentiated glial features, will be assesses. II. Transgenic mouse models: Mice genetically engineered to express exogenous oncogenes in specific cells are now well established as in vivo models for neoplasia in a variety of tissues. Construction of several transgenic mouse lines for investigating glial tumorgenesis is proposed here: First, I will demonstrate the feasibility of directing expression of exogenous genes in glial cells of transgenic mice. Next, i will establish whether directed expression of the SV40 early region genes, or of an oncogenic mutant allele of the p53 tumor suppressor gene, in glial cells if transgenic mice induces neoplasia; I will then classify the histopathology of these tumors. Lastly, I will determine whether malignant progression of glial neoplasia is modeled in these mice.
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