KLF17在子宫Corin表达调控及子痫前期中的作用研究

Preeclampsia is a major disease in pregnancy, afflicting maternal and fetal health. Recently, corin was found to function locally in the pregnant uterus to regulate trophoblast invasion and spiral artery remodeling, which are important for maintaining normal blood pressure in pregnancy. Corin defects may contribute to Preeclampsia. These studies indicate that the transcriptional regulation of corin expression in the pregnant uterus may play a role in the pathogenesis of preeclampsia. In our preliminary studies, we analyzed the corin promotor sequence and identified two Krüppel-like factor (KLF)-binding sites that were critical for corin expression in human endometrial cells. In DNA-binding and luciferase assays, KLF17 was shown to bind directly to the corin promoter and the binding enhanced corin expression in human endometrial adenocarcinoma cells. We also found that KLF17 was up-regulated in the uterus of pregnant mice and decidualized human endometrial stromal cells (HESCs). Disrupting the KLF17 gene prevented corin expression in the HESCs. Based on these results, we hypothesize that KLF17 is a critical transcription factor that regulates corin expression in the pregnant uterus. In this study, we plan to make Klf17 knockout mice, and conduct biochemical, cell biology and mouse model studies to test our hypothesis. Our studies should help to understand the gene control mechanism for uterine Corin expression and its role in preeclampsia. Our studies should help to understand the role of KLF17 in pregnancy and may help to develop new therapeutic approaches to prevent and treat preeclampsia.

子痫前期是危害母婴健康的重大疾病。蛋白酶Corin在妊娠子宫表达升高，在滋养细胞浸润、螺旋动脉重塑和妊娠期血压调控中起重要作用，Corin缺乏可导致子痫前期。妊娠子宫Corin表达调控异常可能是子痫前期的重要病理因素。我们前期研究发现：CORIN基因启动子中含KLF特异性结合位点，转录因子KLF17能与其特异性结合，促进Corin在子宫内膜细胞中表达；妊娠小鼠子宫和蜕膜化诱导的人子宫内膜基质细胞（HESC）中KLF17和Corin表达上调；在HESC中KLF17基因敲除抑制Corin的表达上调。这些结果提示KLF17可能在子宫Corin表达调控中起关键作用。本研究将以KLF17基因敲除小鼠为主要研究对象，以妊娠为切入点，探讨KLF17对子宫Corin的调控作用及其在子痫前期中的作用，以期揭示子痫前期的新机制，为子痫前期的防治提供新思路。

子痫前期是危害母婴健康的重大疾病。蛋白酶Corin在妊娠子宫表达升高，在滋养细胞浸润、螺旋动脉重塑和妊娠期血压调控中起重要作用，Corin缺乏可导致子痫前期。目前尚不清楚妊娠期子宫Corin表达上调的调控机制。我们前期通过人子宫内膜基质细胞（HESC）进行研究，发现转录因子KLF17能与CORIN基因启动子区特异性结合，上调Corin表达水平；KLF17缺乏则抑制Corin的表达。本项目中，我们制备了Klf17基因敲除小鼠，并以此主要研究对象，发现Klf17缺乏阻碍了妊娠子宫Corin的表达上调，且Klf17基因敲除小鼠有子宫螺旋动脉重塑障碍，妊娠高血压及蛋白尿表型。我们的研究结果提示KLF17在子宫Corin表达调控中起关键作用，这也是子痫前期的重要病理机制之一，该研究也为子痫前期的防治提供了新思路。