Analysis of tissue chronic inflammation in adult lifestyle-related diseases and its clinical application

为了分析转录因子KLF5在慢性组织炎症中的作用，我们采用小鼠肾脏炎症模型。首先，我们分析了单侧输尿管梗阻模型（UUO）中KLF 5单倍不足的表型。KLF 5的Halpoinsufficiency显示UUO后炎性单核细胞浸润减少。在该模型中，KLF5控制转录因子CEBPa和KLF5，并诱导CEBPa协同调节分泌蛋白S100A8和S100A9。S100A8和S100A9是KLF5募集炎症单核细胞进入肾脏的效应分子。此外，S100A8、S100A9可诱导UUO后M1巨噬细胞活化。这些结果表明KLF5在肾脏中控制巨噬细胞极性，并在肾损伤后引起肾脏炎症反应。我们发现KLF5、S100A8和S100A9在肥胖小鼠脂肪组织中表达上调。脂肪细胞分泌的S100A8和S100A9使巨噬细胞表型转变为更具炎性的表型。因此，我们认为S100A8和S100A9是一种新的脂肪细胞因子，能够诱导脂肪组织的炎症。为了进一步研究S100A8在体内脂肪组织中的表达，我们利用AP2启动子序列构建了脂肪细胞特异性的S100A8过表达转基因小鼠，并获得了多个品系的转基因小鼠，为S100A8的临床应用奠定了基础。首先，我们考虑将S100A8和S100A9作为肾脏疾病和代谢综合征的新靶基因。但我们在这些实验中分离出了更有希望的候选基因。然而，我们不得不在这种情况下解决这些候选基因的分离。

To analyze the function of transcription factor KLF5 in chronic tissue inflammation, we used the inflammation model of mouse kidney. First, we analyzed the phenotype of haploinsufficiency of KLF5 in unilateral ureteral obstruction model (UUO). Halpoinsufficiency of KLF5 showed reduced infiltration of inflammatory monocyte after UUO. In this model, KLF5 controled transcription factor CEBPa and KLF5 and induced CEBPa cooperatively regulated secretion protein S100A8 and S100A9. S100A8 and S100A9 were effector molecules of KLF5 to recruit inflammatory monocyte into kidney. Moreover, S100A8, S100A9 could induce M1 macrophage activation after UUO. These results indicated KLF5 controlled macrophage polarity in kidney and provoked renal inflammation after renal injury.Next, we analyzed KLF5-S100A8, S100A9 axis in metabolic syndrome. We found KLF5, S100A8 and S100A9 were up-regulated in adipose tissue of obese mice. S100A8 and S100A9 secreted from adipocyte changed macrophage phenotype into more inflammatory phenotype. From these observations, we concluded S100A8 and S100A9 were newly adipocytokine which could induce inflammation of adipose tissue. To further analysis of S100A8 in adipose tissue in vivo, we generated adipocyte specific S100A8 overexpression transgenic mice using AP2 promoter sequence and we have already several lines of transgenic mice.We tried to address the clinical application from these results. First we thought to handle S100A8 and S100A9 as new target genes in kidney disease and metabolic syndrome. But we isolated more promising candidate genes in these experiments. However, we had to settle the isolation of these candidate genes within this occasion.