PE发病中滋养细胞侵袭力受损新机制：PDLIM1通过泛素-蛋白酶体途径降解ACTN4抑制FA复合体动态组装

滋养细胞侵袭力受损是子痫前期（PE）发病的关键点。最新研究发现PDLIM1通过与ACTN4结合，调控肿瘤细胞侵袭和转移。敲低ACTN4显著抑制滋养细胞侵袭。前期工作发现在PE胎盘组织中PDLIM1表达增加，ACTN4表达降低，PDLIM1调控ACTN4蛋白的泛素化水平，而ACTN4通过黏着斑调控滋养细胞侵袭力。我们推测：PDLIM1表达异常增加，促进泛素-蛋白酶体途径降解ACTN4，进而抑制FA复合体的动态组装，最终导致滋养细胞侵袭力受损，血管重塑障碍，PE发病。本项目以PDLIM1为研究对象，滋养细胞侵袭力受损为切入点。拟在临床标本、细胞模型以及动物模型上，应用分子生物学和基因工程等方法，从“胎盘组织-细胞模型-动物模型”全面验证该假说，将为深入研究PE的发病机制提供新思路。

The impaired invasion of trophoblasts is the key factor to preeclampsia (PE) pathogenesis. Recent study demonstrated that PDLIM1 is involved in regulating cancer cells invasion and metastasis by interacting with ACTN4. In addition, our published article found that silencing of ACTN4 could inhibit trophoblast invasion. The preliminary data have found that PDLIM1 is upregulated, and ACTN4 is downregulated in PE placenta. Meanwhile, PDLIM1 can regulate the ubiquitination level of ACTN4 protein, and ACTN4 may participate in regulating trophoblast invasion through the focal adhesion. Therefore, we hypothesize that abnormal upregulation of PDLIM1 in trophoblast can promote the degradation of ACTN4 by the ubiquitin-proteasome pathway. As a consequence, the dynamic assembly of FA complex is inhibited. These result in the impaired invasion of trophoblast cells, and defected vascular remolding, which leads to the occurrence of PE. To provide the novel insight into PE pathogenesis, we employ PDLIM1 as the research object, with impaired trophoblast invasion as the starting point. Numerous approaches such as molecular biology and genetic engineering will be applied on the placenta-cell-animal models to further verify our hypothesis.