Identification of the posttranscriptional regulatory network of the pro-inflammatory cytokine HMGB1

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The eradication of pathogenic infection is accomplished by the activation of immune responses in individuals. Although beneficial, the aberrant activation of these responses may cause deleterious consequences which can ultimately be detrimental. These immune responses are mediated by factors named cytokines which are produced predominately by white blood cells of the immune system. One such factor, named High Mobility Group Box1 (HMGB1), as recently been shown to play a pronominal role in the pathogen induced immune response. The generation of protein from DNA requires the synthesis of an intermediate molecule named RNA. RNA thus serves as a template from which DNA genes are converted into proteins. The generation of protein from RNA is mediated by proteins named RNA binding proteins. Our laboratory is working on an RNA binding protein named HuR and our preliminary data indicate that this protein is involved in the regulation of HMGB1 mRNA. The purpose of this proposal is to identify all sequences in the HMGB1 mRNA mediating its expression in white blood cells and determine consequently the network of RNA binding proteins which, in addition to HuR, regulate the expression of HMGB1. Determining the mechanisms through which these RNA binding proteins regulate the HMGB1 mRNA may enable the identification of identify potential anti-inflammatory compounds which may lower the morbidity and mortality associated to exuberant cytokine production.