Sepsis, traumatic injury, injury complicated by infection, and major surgery all initiate systemic responses that follow release of complex and varied combinations of cytokines and stress hormones, as well as of bacterial endotoxins in infection. In extreme conditions, these responses can result in death due to organ dysfunction and multiple organ failure. Major changes in arginine metabolism are major hallmarks of these pathophysiologic states. These changes include dramatic increases in expression of the arginases (isoforms I and I1), which can have a significant impact not only on NO synthesis but also on synthesis of polyamines and proline, which are involved in cell proliferation and wound healing. We have shown that transcription of the arginase genes exhibits a complex pattern of responses to a wide variety of pro- and anti-inflammatory stimuli. It is particularly notable that responses of the arginases and iNOS to these stimuli are not identical. A clear understanding of the complex changes in arginine metabolism, as well as of the mechanisms underlying the responses to the complex combinations of pro- and anti-inflammatory cytokines and other agents, is essential for advances in the prevention or reversal of multiple organ failure. To elucidate these mechanisms, we propose the following aims:
AIM I. To define the promoter elements and cognate transcription factors responsible for regulation of the arginase I gene-by pro- and anti-inflammatory agents.
AIM II. To define the promoter elements and cognate transcription factors responsible for regulation of the arginase II gene by pro- and anti-inflammatory agents.
AIM III. To define mechanisms involved in regulation of arginase II mRNA stability. In each of these aims, we will test specific hypotheses regarding transcriptional regulation of the arginase genes by individual stimuli and combinations thereof. Elucidation of the mechanisms involved in regulation of arginase gene expression, combined with independent efforts by others to elucidate the mechanisms involved in regulation of the iNOS gene, will greatly enhance our understanding of the molecular events underlying the pathophysiology of sepsis and trauma and thus aid in design of therapeutic strategies for these disease states.
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| Gray, Michael J; Poljakovic, Mirjana; Kepka-Lenhart, Diane et al. (2005) Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta. Gene 353:98-106 |
| Morris Jr, Sidney M (2004) Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care 7:45-51 |
