C/EBP ALPHA REGULATION OF ACUTE PHASE RESPONSE IN VIVO

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The nuclear transcription factor C/EBPalpha has an important role in the expression of genes regulating energy mtetbolism, in the differentiation and maturation of lung and adipose tissues, and in the acute phase, or inflammatory response as demonstrated in a knockout mouse model for C/EBPalpha generated in our laboratory. The long term goals of this application are to determine the molecular basis for the transcriptional regulation of acute phase genes in the newborn animal which our in vivo studies of the mutant mice show is dependent on expression of c/EBPalpha. We will examine several molecular mechanisms by which C/EPB alpha may regulate this primary inflammatory response in order to define C/EPB alpha 's role in this pathway. The specific aims include characterization of other transcription factors known to regulate the acute phase response to determine whether their activity is dependent on C/EBP alpha. Cytokine signaling pathways will be examined in the newborn animals to determine whether these responses are altered by the loss of C/EBP alpha expression. Finally, we will test whether mutations of the C/EBP alpha protein that lack the ability to heterodimierize and/or interact with NFkappaB will be able to restore the acute phase response in order to distinguish between the DNA molecular basis for altered C/EBPbeta mRNA translation I the absence of C/EBP alpha. These studies stem from the unexpected observation that the C/EBPbeta protein isoforms that result from multiple translation initiation start sites are very different in the livers of C/EBPalpha knockout newborns compared to the normal littermates. This observation reveals a new activity for C/EBPalpah; that of a regulator of C/EBPbeta mRNA translation initiation.