The p53 protein is a site-specific transactivator or repressor of transcription that promotes apoptosis, in part, by modulating the expression of select target genes. Studies have implicated p53 in the pathogenesis of neuronal cell death occurring after DNA damage orexcitotoxicity, or in neurodegenerative diseases such as Huntington?s Disease and Alzheimer?s Disease. However, the cellular consequences of p53 activation in neurons are poorly understood, and a comprehensive survey of changes in gene and protein expression in neurons after p53 activation is therefore needed. This project will combine the use of cDNA microarray technology and Fourier transform ion cyclotron resonance mass spectrometric analysis of the proteome to rapidly and comprehensively characterize p53-dependent changes in mRNA and protein expression in cortical neurons derived from p53+/+ and p53-/- mice after genotoxic or excitotoxic injury. Proteins essential to p53-mediated neuronal cell death will be identified and investigated further to elucidate their function. One such gene product, Peg3, is a Kruppel-type zinc finger protein and putative transcription factor that has recently been implicated in p53-mediated apoptosis in fibroblasts. Using transient transfection or exposure to DNA damaging agents, Peg3 expression will be manipulated in cortical neurons derived from wild type, p53-/- or bax-/- mice, and the effects on neuronal cell death will be assessed. The study of Peg3 will serve as a model for the investigation of other p53-regulated gene products in neurons. The candidate has earned both the M.D. and Ph.D. degrees from Harvard Medical School, and is now nearing completion of a residency in neurosurgery at the University of Washington, where he has recently been appointed as an Acting Instructor. The proposed research represents a continuation of the candidate?s longstanding interest in the physiology and survival of neurons. The skills acquired will assist the candidate in establishing an independent research career to study the determinants, of neuronal survival, differentiation and function.
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