C/EBP ALPHA REGULATION OF ACUTE PHASE RESPONSE IN VIVO

核转录因子C/EBPalpha在细胞凋亡中具有重要作用。 调节能量代谢的基因的表达， 分化和成熟的肺和脂肪组织，并在 急性期或炎症反应，如基因敲除所示 在我们的实验室中产生的C/EBPalpha小鼠模型。 长 本申请的术语目标是确定用于制备纳米颗粒的分子基础。 新生儿急性期基因的转录调控 我们对突变小鼠的体内研究表明， 对c/EBPalpha表达的影响。 我们将检查几个分子 C/EPB α可能调节这种主要的 炎症反应，以确定C/EPB α的作用， 通路 具体目标包括： 已知调节急性期反应的转录因子， 确定它们的活性是否依赖于C/EBP α。 将在新生动物中检查细胞因子信号通路 以确定这些反应是否因C/EBP缺失而改变 alpha表达式 最后，我们将测试是否突变的 缺乏异二聚化能力的C/EBP α蛋白和/或 与NF κ B相互作用将能够恢复急性期 反应，以区分DNA分子基础， 改变C/EBP β mRNA翻译I缺乏C/EBP α。 这些研究源于一个意想不到的观察， 由多重翻译产生的C/EBP β蛋白亚型 C/EBPalpha的肝脏中的起始位点非常不同 基因敲除的新生儿与正常同窝出生的新生儿相比。 这 观察揭示了C/EBPalpah的新活性;调节剂的活性 C/EBP β mRNA翻译起始。

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.