BMP6调控滋养细胞侵袭在子痫前期发病中的作用及机制

滋养细胞侵袭不足导致胎盘发育异常是子痫前期发病的主要原因之一。骨形态发生蛋白6（BMP6）作为一种分泌型多功能蛋白在人胎盘组织中表达丰富，但其在滋养细胞侵袭和子痫前期中的作用尚不清楚。我们的前期工作发现，子痫前期胎盘中BMP6的表达显著降低，且与患者血压水平呈显著负相关。进一步研究发现BMP6促进滋养细胞侵袭力，同时增加侵袭相关转录因子JUNB和胎盘生长因子PlGF的表达。据此，我们推测滋养层BMP6表达不足可能通过减少JUNB和PlGF表达损害滋养细胞侵袭和胎盘发育，进而导致子痫前期的发生。本课题拟利用滋养细胞类器官、动物、细胞实验模型和临床样本，阐明BMP6调控滋养细胞侵袭的作用和分子机制，明确妊娠早期血清BMP6表达水平与子痫前期发生进展的相关性，探讨应用靶向BMP6通路药物防治子痫前期的效果。本课题旨在丰富子痫前期病因机制，为子痫前期早期筛查方案和精准防治药物的开发提供新靶点。

Insufficient trophoblast invasion-induced placentation dysregulation is one of the leading causes of pre-eclampsia. Bone morphogenetic protein 6 (BMP6), as a secreted multifunctional protein, is abundantly expressed in human placental tissues. However, the roles of BMP6 in trophoblast invasion and pre-eclampsia occurrence are still unknown. Our recent research has demonstrated the decreased expression of BMP6 in pre-eclamptic placentae compared to normal placentae. Besides, the expression levels of BMP6 are negatively correlated with the blood pressure levels of pre-eclampsia patients. Our further experiments demonstrated that BMP6 promoted trophoblast invasion and increased the expression of invasion-related transcription factor JUNB and placental growth factor (PlGF) in trophoblast cells. Based on these findings, we herein hypothesized that decreased BMP6 expression in placental trophoblast cells might impair trophoblast invasion and placentation through down-regulating JUNB and PlGF, contributing to the occurrence of pre-eclampsia. By utilizing ex vivo, in vivo, and in vitro experimental models (3D trophoblast organoid model, pre-eclamptic rat model, and cell models) and clinical samples, our current project aims to elucidate the roles and molecular mechanisms of BMP6 in regulating trophoblast invasion process, clarify the correlation between serum BMP6 expression levels in early pregnancy and the development as well as progression of pre-eclampsia, and examine the effectiveness of BMP6 targeting drugs in preventing and treating pre-eclampsia-related phenotypes. This project aims to enrich the etiology and underlying mechanisms of pre-eclampsia, as well as provide new molecular targets for developing precise clinical diagnostic and therapeutic approaches.