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Multiple sclerosis and other myelin diseases affect the quality of life many people. In the United States alone, multiple sclerosis afflicts as many as 400,000 individuals. Myelin, which is attacked by multiple sclerosis, plays a critical role in maintaining the healthy function of the adult nervous system. There are many model systems that study myelin and its formation and loss. Our lab investigates the cuprizone model of demyelination and remyelination. The cuprizone model is commonly believed only to affect adult oligodendrocytes, which it kills. The current study investigates whether other cells in the oligodendrocyte line, such as oligodendrocyte progenitor cells, might also be susceptible to the toxic effects of cuprizone. Oligodendrocyte progenitor cells may play an important role in repairing and replacing myelin after demyelinating insults. So any effect that the model has on these cells may be relevant to the use of the model for studying remyelination. In order to evaluate the potential effects of cuprizone, dividing cells in adult mice were labeled with the proliferation marker, Bromodeoxyuridine (BrdU). Immunohistochemical labeling of BrdU shows that the number of actively dividing cells seen in the subventricular and subgranular zones sharply and dramatically decreases after just 1 week on cuprizone. In the following weeks, the number of dividing cells increases, but even after 3 weeks of recovery without cuprizone, the number of BrdU+ cells does not return to control levels. These results may have significant ramifications in the interpretation of results obtained from the cuprizone model, and this finding must be considered in selecting a model for future demyelination studies.

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Gliomas are the most common primary tumors of the central nervous system believed to arise from glial cells. Invasive growth and inherent propensity for malignant progression make gliomas incurable despite extensive treatment. I have developed a life-like orthotopic glioma model and used this and other in vivo models to study basic mechanisms of glioma development and treatment. Previous studies had indicated that experimental gliomas could arise from glial stem cells and astrocytes. The present thesis describes the making and characterization of a novel mouse model, Ctv-a, where gliomas are induced from oligodendrocyte progenitor cells (OPCs). Our study shows that OPCs have the capacity to give rise to gliomas and suggests in light of previous data that the differentiation state of the cell of origin affects tumor malignancy. CDKN2A encodes p16INK4a and p14ARF (p19Arf in mouse) commonly inactivated in malignant glioma. Their roles in experimental glioma have been extensively studied and both proteins have tumor suppressor functions in glial stem cells and astrocytes. Here, we demonstrate that p19Arf only could suppress gliomagenesis in OPCs while p16Ink4a had no tumor suppressive effect. Functional DNA repair is pivotal for maintaining genome integrity, eliminating unsalvageable cells and inhibiting tumorigenesis. We have studied how RAD51, a central protein of homology-directed repair, affected experimental glioma development and have found that expression of RAD51 may protect against genomic instability and tumor development. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a central feature of malignant progression in glioma. Antiangiogenic treatment by inhibition of vascular endothelial growth factor receptor signaling is used in the clinic for treatment of some cancers. We have investigated the effect of an alternative antiangiogenic protein, histidine-rich glycoprotein (HRG), on glioma development and found that HRG could inhibit the formation of malignant gliomas and completely prevent the formation of glioblastoma.

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