HSF1对子痫前期的保护作用及分子机制研究

Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies world-wide. Preeclampsia is a severe complication of pregnancy characterised by increased maternal blood pressure, proteinuria, and end organ disease due to systemic vascular/endothelial dysfunction. Although hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is thought to be a major cause of preeclampsia, how hypoxia affects placental development remains uncertain. Revealing its mechanism of pathogenesis and development is desperately required for developing new therapeutic approaches. In recent years, the function of heat shock factor 1 (HSF1) in diverse disease has been attracted increasing attentions. However, the expression and function of HSF1 in preeclampsia has been barely studied. In our preliminary study, we have found that the expression level in preeclampsia is lower than in the normal pregnant women. Furthermore, we also revealed that HSF1 could regulate the cell apoptosis through regulating the PTEN/AKT pathway, which is an important cellular pathway controlling cell apoptosis. .It has been demonstrated that HSF1 orchestrates the expression of genome-wide genes, however, the uncovered function of HSF1 is focused on regulating the expression of coding genes. Our previous work revealed that the regulating function of HSF1 is beyond coding genes, and found that the expression of a serie of lncRNA is related with the expression of HSF1. It suggested that HSF1 might also be capable of regulating lncRNAs..Encouraged by those interesting results, we would like to propose this project to extend our studies for investigating the function of HSF1 in preeclampsia pathogenesis and development, and demonstrating its action mechanism in controlling the properties of trophoblast cells..We plan to 1) detect the HSF1 expression in preeclampsia patients at different grades; 2) investigate the cellular functions of HSF1 in controlling cell apoptosis through PTEN/AKT pathway; 3) study the regulating mechanism of HSF1 on the biogenesis of lncRNAs in preeclampsia. Our final goal is demonstrating the cellular functions of HSF1 in preeclampsia and uncovering its action mechanisms. .The success of this project will help us to better understand the pathogenesis and development mechanism of preeclampsia, and to further develop novel therapeutic and diagnostic target gene against preeclampsia.

子痫前期严重威胁着全球女性的健康，而对其发病及发展机制的深入理解是诊疗子痫前期的基本要求。热休克因子1（heat shock factor 1, HSF1）在调控应激相关基因和疾病发生发展中的作用是近年来广受关注的研究热点，但其在子痫前期中的功能却鲜有报道。我们已发现HSF1与多个疾病的发生发展有密切相关性；证实子痫前期患者中存在HSF1的表达异常，并且HSF1能够通过PTEN/AKT通路影响细胞凋亡；此外已在一种细胞模型中鉴定出多条与HSF1表达具有强相关性的lncRNAs。本课题将在已有工作基础上进一步分析子痫前期母体及胎盘组织中HSF1的表达；研究在缺氧条件下HSF1参与保护滋养层细胞的分子机制和对包括PTEN/AKT在内的信号途径的调控作用；并解析HSF1在子痫前期模型中对lncRNAs表达的调控作用。本研究将为子痫前期的发病机制和HSF1在子痫前期中的生物学作用提供新的理论基础。

子痫前期严重威胁女性健康，而对其发病发展机制的深入理解是诊疗子痫前期的基本要求。热休克因子1（heat shock factor 1, HSF1）在调控应激相关基因和疾病发生发展中的作用是近年来广受关注的研究热点，但其在子痫前期中的功能却鲜有报告。本项目分析了子痫前期胎盘组织中HSF1的表达，研究在缺氧条件下HSF1参与保护滋养层细胞的分子机制和对包括PTEN/AKT在内的信号途径的调控作用，解析HSF1在子痫前期模型中对长链非编码RNA（lncRNA）表达的调控作用。.我们通过对比分析了正常及子痫前期患者胎盘组织中HSF1蛋白的表达情况，发现HSF1在胚胎组织中主要表达在滋养层细胞中，并且子痫前期组的表达量低于正常对照组。利用CoCl2处理模拟缺氧环境，在体外滋养层细胞中构建了缺氧模型，证明缺氧处理可以降低HSF1的表达水平、抑制细胞增殖活性。分别通过过表达、敲减HSF1，阐明HSF1对滋养层细胞具有重要的保护作用。机制研究发现HSF1对PTEN/AKT通路、缺氧诱导因子（hypoxia inducible factor-1，HIF-1）活性亚基HIF1α的调控功能，初步揭示了HSF1对滋养层细胞保护的作用机制。结合生物信息学预测分析与分子生物学机制研究，证实HSF1对长链非编码RNA的调控作用，并且发现其中一条lncRNA在子痫前期中的表达伴随HSF1发生改变，提示这一调控通路在子痫前期模型中具有其独特的生物学作用。对于揭示HSF1在子痫前期中的生物学作用机制具有重要的理论价值。建立的体外缺氧模型与体内HSF1基因操作系统均为我们继续深入研究HSF1在缺氧条件下对滋养细胞的保护作用及生物学机制提供了坚实基础。.本项目通过对子痫前期中HSF1的生物学作用研究，结合前期研究结果，证明HSF1在子痫前期中可以通过对下游编码基因、非编码microRNA、非编码lncRNA的三种调控作用发挥重要作用。通过初步阐明HSF1在缺氧条件下对滋养层细胞的保护作用，为理解子痫前期的发病机制及治疗策略开发提供了新的提供新的线索和切入点。.本项目组发表标注本基金资助的SCI文章3篇、国内期刊论文1篇，另有一篇文章正在总结、撰写、投稿准备中。