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

病原性感染的根除是通过激活个体的免疫反应来完成的。虽然有益，但这些反应的异常激活可能会导致有害的后果，最终可能是有害的。这些免疫反应是由称为细胞因子的因子介导的，这些因子主要由免疫系统的白细胞产生。其中一个被称为高迁移率组盒1(HMGB1)的因子，最近被证明在病原体诱导的免疫反应中起着代名词作用。从DNA中产生蛋白质需要合成一种名为RNA的中间分子。因此，RNA充当了DNA基因转化为蛋白质的模板。从RNA产生蛋白质是由一种名为RNA结合蛋白的蛋白质介导的。我们实验室正在研究一种名为HUR的RNA结合蛋白，我们的初步数据表明，该蛋白参与了HMGB1 mRNA的调节。本研究的目的是确定HMGB1基因在白细胞中表达的所有序列，并据此确定除HUR外还调节HMGB1表达的RNA结合蛋白网络。确定这些RNA结合蛋白调节HMGB1 mRNA的机制可能有助于识别潜在的抗炎化合物，从而降低与旺盛的细胞因子产生相关的发病率和死亡率。

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.