We are investigating the cellular mechanisms of neurodegenerative disorders and brain tumors mediated by oxidative stress and iron mismanagement. Iron is tightly regulated for normal function. When iron imbalance occurs by dysfunction of iron regulatory mechanisms, cells are subjected to a pro-oxidative stress and a pro-inflammatory environment. HFE is one of several iron regulatory proteins and polymorphisms in the HFE gene are prevalent in Caucasians. HFE gene variants have been traditionally associated with the iron overload disorder known as Hereditary Hemochromatosis. Recently, it has become clear that the two most common variants in the HFE gene, H63D and C282Y, may be risk modifiers for neurodegenerative disorders (Alzheimer's disease, Amyotrophic Lateral Sclerosis) and cancer, respectively. The following lists are my research interests. First, understand the cellular consequences of carrying variant forms of HFE in brain tumors and neurodegenerative disorders. Second, determine the frequency of HFE polymorphisms in brain tumor patients and neurodegenerative disorders. Third, determine the chemotherapy resistance mechanism in the C282Y-expressing tumor cells. Fourth, develop a new chemotherapeutic agent to treat brain tumors, especially Temodar-resistant brain tumors, and neurodegenerative disorders that express HFE gene variants. For these studies, we utilize both cell culture and animal models. We are using stably-transfected human neuroblastoma cell lines that express different forms of HFE, and human astrocytoma cell lines expressing different HFE variants to determine the cellular consequences of the variants forms of HFE. We are also using H63D and C282Y knock-in mice to determine the consequence of HFE variants in in vivo.