长链非编码RNA GAS5竞争性结合孕激素受体PR-A参与分娩发动机制研究

Abnormal parturition leads to premature and delayed delivery,and it is harmful to the mother and baby. The regulation of uterine muscle contractions plays an important role in parturition and the prevention and treatment of premature and delayed delivery. "Functional progesterone withdrawal" is one of the important mechanisms regulating uterine muscle contractions. We have reported that the regulation of nuclei progesterone receptor (PR)-A played a crucial role in uterus contraction during parturition. However,the mechanism of PR-A relocates into the nucleus is unknown. Our previous study have found that there was 6.67 times lower expression of long noncoding RNA (lncRNA) GAS5 in in-labor myometrium than the not in-labor ones by lncRNA chips and quantitative PCR analysis. Further researches suggested GAS5 have an effect on nuclei PR-A expression. Previous study have reported that GAS5 could inhibit transcriptional activity of glucocorticoid receptor (GR) by competitively binding to it, and GR and PR have the similar protein structure. Accordingly, we are proposing an assumption:the decreased expression of GAS5 in myometrium causes its PR-A competitive capacity reduction, and increases more PR-A entering to the nucleus, which promotes uterus contractions. We brought GAS5 into the mechanism study of parturition to clarify "functional progesterone withdrawal " mechanism. So it is hopeful to provide a theoretical basis for premature and delayed delivery prevention in the future.

分娩发动异常导致早产或过期产，对母儿危害极大。子宫肌收缩调控机制是分娩发动的重要研究对象，对早产及过期产防治有指导意义。“功能性孕激素撤退” 是调控子宫肌收缩的重要机制之一。课题组前期报道细胞核孕激素受体（PR）-A影响收缩基因表达参与分娩发动，而PR-A进入细胞核的调控机制不清。通过长链非编码RNA（LncRNA）芯片及定量检测发现GAS5在临产子宫肌中稳定6.67倍低表达，进一步研究提示GAS5可影响PR-A核内表达量。文献报道GAS5通过竞争性结合糖皮质受体（GR）影响其转录活性,GR与PR蛋白结构相似。据此，课题组推测：分娩发动时子宫肌中GAS5竞争性结合PR-A能力降低，导致PR-A核内再定位及收缩基因表达，促进子宫肌收缩。本课题将GAS5引入分娩发动机制研究中，进一步阐明“功能性孕激素撤退机制”，为分娩发动机制研究提供新突破点，并为临床早产及过期产防治提供理论依据。

分娩发动异常导致早产或过期产，对母儿危害极大。子宫肌收缩调控机制是分娩发动的重要研究对象，对早产及过期产防治有指导意义。“功能性孕激素撤退” 是调控子宫肌收缩的重要机制之一。课题组前期报道细胞核孕激素受体（PR）-A影响收缩基因表达参与分娩发动，而PR-A进入细胞核的调控机制不清。通过长链非编码RNA（LncRNA）芯片及定量检测发现GAS5在临产子宫肌中稳定6.67倍低表达，进一步研究提示GAS5可影响PR-A核内表达量。文献报道GAS5通过竞争性结合糖皮质受体（GR）影响其转录活性,GR与PR蛋白结构相似。据此，课题组推测：分娩发动时子宫肌中GAS5竞争性结合PR-A能力降低，导致PR-A核内再定位及收缩基因表达，促进子宫肌收缩。本课题将LncRNA GAS5引入分娩发动机制研究中，从临床水平、原代子宫肌细胞水平等多方面进行实验设计，最终结果提示：在分娩发动过程中GAS5低表达导致子宫肌细胞收缩功能增强;子宫肌细胞中GAS5通过竞争性结合PR-A，分娩发动时低表达的GAS5促使更多PR-A蛋白入核，促进子宫肌收缩，参与分娩发动机制。迄今，长链非编码RNA在分娩发动作用机制中的研究尚未见报道，本研究率先阐明“功能性孕激素撤退机制”，将基础与临床有机结合，为分娩发动机制研究提供新突破点，并为临床早产防治提供理论依据。