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.
Although patient age is arguably the most robust factor for survival glioma, the mechanisms underlying the negative impact of increased age on treatment responses and malignancy are completely unknown. Since p53, the central regulator of DNA integrity, is markedly decreased in aged neural progenitor cells (cells of glioma origin), we hypothesize that decreased p53 with age results in increased mutations and higher degree of tumor malignancy. Using a new mouse model where p53 can be eliminated from neural progenitor cells we will definitively confirm our hypothesis, provide new tools to model gliomas and facilitate future discovery of new treatments that account for the impact of aging on tumor malignancy and treatment resistance.
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|Stoll, Elizabeth A; Horner, Philip J; Rostomily, Robert C (2013) The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment. Aging Cell 12:733-41|
|Mikheev, Andrei M; Ramakrishna, Rohan; Stoll, Elizabeth A et al. (2012) Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy. Aging Cell 11:1027-35|
|Mikheev, Andrei M; Stoll, Elizabeth A; Ramakrishna, Rohan et al. (2012) Geropotency: increased malignant potential of aging neural progenitors. Aging (Albany NY) 4:854-5|