RhoGDI1和RhoGDI2对滋养细胞迁移侵袭的影响及机制的研究

Placental trophoblasts undergo a complex process of proliferation, migration, and differentiation. Failures in this process can lead to clinical pathological conditions, including miscarriage , intrauterine growth retardation and preeclampsia. The process of placentation bears a striking similarity to tumor cell metastasis. The family of Rho guanosine diphosphate dissociation inhibitors (RhoGDIs) that include RhoGDI, RhoGDI2, and RhoGDI3.In our study ,we found that RhoGDI2 inhibits trophoblast cell migration, and this function may involve suppression of RAC1 activation. We considered that RhoGDI1 and RhoGDI2 might also have an important role in the placenta. We want to assess the effects of RhoGDI1 and RhoGDI2 on the migration of a human extravillous trophoblast (EVT) cell line, and whether through Rho family-PI-3K/AKT-NF-κB pathway , in order to offer theoretical basis of treatment of miscarriage , intrauterine growth retardation and preeclampsia.

滋养细胞迁移和侵袭能力下降是子痫前期/子痫、不明原因流产、胎儿生长受限等妊娠相关性疾病的重要原因。正常的滋养细胞也被称为假恶性细胞。因此，许多肿瘤细胞的生物学行为的发生机制同样适用于对滋养细胞生物学行为的解释。RhoGDIs家族主要包括RhoGDI1、RhoGDI2和RhoGDI3。目前RhoGDI家族的成员中研究较多的是RhoGDI1和RhoGDI2 ，并且关于他们的研究主要集中在肿瘤细胞上。我们前期的研究发现RhoGDI2对滋养细胞的迁移起着抑制的作用。本课题将研究RhoGDI1和RhoGDI2对滋养细胞功能的影响，明确是否通过RhoGDI1和RhoGDI2-Rho家族蛋白-PI-3K/AKT-NF-κB这一途径影响滋养细胞的迁移侵袭，为防止滋养细胞迁移侵袭异常引起的孕早期流产、子痫前期重度等疾病的治疗提供理论基础。

本项目基本按照计划进行，大体原则和方向不变。1、首先在组织学中探讨了RhoGDI1及RhoGDI3的表达情况，发现相对于正常的胎盘组织，在子痫前期胎盘中RhoGDI1和RhoGDI3的表达均下降，说明RhoGDI1及RhoGDI3可能与子痫前期疾病的发生相关2、成功构建RhoGDI1的干扰RNA病毒，探讨RhoGDI1对滋养细胞功能的影响，发现RhoGDI1 siRNA抑制滋养细胞的迁移及侵袭，抑制滋养细胞的增殖，促进滋养细胞的凋亡，并且通过抑制MAPK、PI3K/AKT及Src信号通路，抑制滋养细胞的迁移侵袭。3、通过基因芯片及蛋白验证发现了RhoGDI1下游调控的三个重要蛋白DUSP1、PIM1及HSPA1A 。4、RhoGDI2抑制滋养细胞的迁移，证实了RhoGDI2通过影响RAC1的活性影响滋养细胞的迁移。5、发现RhoGDI1和RhoGDI2对滋养细胞的迁移作用是相反的。.本课题目前已发表课题相关第一作者中文文章1篇，其他相关论文2篇。本研究深入的探讨了RhoGDI家族对滋养细胞生物学的影响及下游调节通路，为早期流产、子痫前期重度等疾病的治疗提供理论基础。