Despite multimodality therapy including surgery, radiation therapy and chemotherapy, the median survival for patients presenting with glioblastma multiforme remains < 1 year. Novel therapeutic approaches are urgently needed. The PI hypothesizes that polyunsaturated fatty acids (PUFAs) may represent an exciting alternative. PUFA-enrichment of glioma cells leads to increased free radical generation, tumor cell cytotoxicity and an increased radiosensitivity; normal cell growth and radiosensitivity are unaffected. Moreover, the antioxidant enzyme catalase in normal rat brain microvascular endothelial cells (RBMECs) and astrocytes is upregulated by PUFAs; glioma catalase levels do not increase significantly. The PI hypothesizes that this ability of PUFAs to selectively modulate catalase gene expression reflects selective activation of the peroxisomal proliferator-activated receptor (PPAR), retinoic acid receptor (RAR) and/or retinoid X receptor (RXR) nuclear hormone receptors (NHRs) with resultant upregulation of catalase gene expression. To test this hypothesis he will I] map regions of the rat catalase promoter that contain putative PUFA responsive cis-elements that may participate in governing the expression of catalase using transcriptional reporter assays with promoter-reporter deletion constructs of the catalase gene, ii] use gel mobility shift assays to characterize the binding of NHRs to putative response elements identified in the rat catalase promoter region and determine constitutive expression of the alpha, beta and gamma isotypes of PPAR, RAR and RXR NHRs in RBMECs, primary astrocytes and glioma cells; iii] investigate the role of particular eicosanoids in mediating the PUFA-induced upregulation of catalase in RBMECs and rat astrocytes by determining if pre-incubation of these cells with PUFA in the presence of cyclooxygenase, lipoxygenase or cytochrome P-450 inhibitors abrogates the PUFA-mediated increase in catalase gene expression. In addition, he will test the significance of these PUFA-mediated effects in vivo by I] evaluating the anti-glioma properties of PUFAs using a well-defined rat glioma model; ii] evaluate the ability of PUFAs to modulate in vivo normal brain catalase levels and determine if this increase leads to reduced radiation-induced brain injury. Defining the molecular basis for the tumor cytotoxic effect of PUFAs and the potential protection of normal cells, via upregulation of catalase, will lead to the development of novel therapies that offer the promise of significantly improving long-term cure and survival rates for an aggressive and often fatal neoplasm.
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