The transgenic mouse model for reversible activation of physiological levels of p53 will be used to investigate the contribution of the loss of the p53 pathway to brain tumor formation and growth with the long-term goal of evaluating the therapeutic potential of this tumor suppressor for glioma treatment.
The specific aims are 1) to determine whether re-activation of p53 can prevent, retard or reverse carcinogen-induced brain tumors in mice and to elucidate which attribute of p53 function affects gliomagenesis; 2) to define molecular lesions required for gliomagenesis and investigate the role of p53 in modulating glioma invasion; 3) to engineer conditional transgenic mice models for oncogene-induced glioma formation and to determine the role of p53 in this process. The consequences of p53 re-activation in the brain tumors that developed without active p53 will be monitored by MRI. CGH analysis will be employed to detect genomic alterations required for glioma occurrence. The microdissection of brain tissue and subsequent microarray analysis will reveal the spectrum of p53 response in vivo during the various stages of glioma formation. Overall, the proposed research will significantly contribute to the understanding of gliomagenesis.
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