Chronic versus acute effects of p53 deletion on Olig2 progenitor malignancy

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Human gliomas are a nearly uniformly fatal disease and little improvement in outcome has been realized in over 25 years. Although arguably the most important prognostic factor for glioma risk, survival, malignancy and treatment resistance, aging has not been incorporated into routine pre-clinical models and the underlying mechanisms responsible for the negative effects of aging are not known. Here we propose to follow up on our previous novel observation that glioma malignancy in a mouse model is primarily dependent on age-related cell intrinsic factors. Among potential candidate mechanisms, we discovered that a chronic decline in p53 activity with aging in neural progenitor cells (NPCs), associated with increased genomic instability, may in part account for this effect. Therefore we propose to develop a novel mouse model system whereby p53 can be deleted from Olig2 expressing NPCs after exposure to tamoxifen in a temporal fashion. This will permit the unambiguous determination of how chronic versus acute p53 deletion affects the malignant potential of Olig2 NPCs (putative glioma cells of origin) and associated effects on genomic instability. We expect to demonstrate that this versatile model system will facilitate validation of our hypothesis that chronic loss of p53 function, as occurs with aging, enhances genomic instability and malignant potential in NPCs. In keeping with the R03 mechanism, the completion of these self-contained studies will provide valuable new research tools and data for future studies of general importance in many fields of neurobiology and nervous system disease.