Transcriptional Control of Human Placental Differentiation

描述(申请人提供)：在人类胎盘的发育过程中，单核细胞滋养层细胞(CTB)增殖并融合形成合体滋养层细胞(STB)表型。尽管这一分化过程对成功妊娠至关重要，但调节这一过程的分子机制却知之甚少。我们的实验室利用人CTB细胞分化的体外模型，已经证明转录因子AP-21对于绒毛CTB细胞向STB表型的分化至关重要；我们已经表征了AP-21的一些上游调节因子和下游靶点。我们的初步研究表明，几种诱导CTB细胞分化的细胞外因素刺激AP-21的表达，Wnt-β-catenin-TCF途径在CTB细胞分化过程中抑制AP-21的表达，严重子痫前期患者的胎盘中AP-21的表达异常。我们现在建议在正常分化和以绒毛CTB分化异常为特征的病理条件下，如先兆子痫和IUGR，全面研究AP-21调节CTB细胞向STB细胞分化的机制。特异性目标1验证了诱导绒毛CTB分化的细胞外因子至少部分地通过AP-21依赖的机制起作用的假说。目的2验证AP-21和Wnt-2-catenin途径之间存在负反馈回路，以及诱导CTB细胞分化的细胞外因子至少部分通过抑制Wnt-2-catenin-TCF信号而发挥作用的假说。目的3验证AP-21级联异常至少部分导致子痫前期和IUGR绒毛CTB细胞分化缺陷的假说。这些实验将利用一种人体CTB细胞分化的体外模型，该模型非常接近于体内的分化过程。分化的程度将通过细胞形态和特定的STB标记基因的表达来监测。这些研究将为胎盘分化的分子机制以及先兆子痫和宫内发育迟缓胎盘缺陷的发病机制提供新的见解。这些洞察力反过来可能导致开发新的策略来治疗导致胎儿发病率和死亡率的胎盘缺陷。

DESCRIPTION (provided by applicant): During the development of the human placenta, mononuclear cytotrophoblast (CTB) cells proliferate and fuse to form a syncytiotrophoblast (STB) phenotype. Although this differentiation process is critical for a successful pregnancy, the molecular mechanisms that regulate the process are poorly understood. Our laboratory, utilizing an in vitro model of human CTB cell differentiation, has shown that the transcription factor AP-21 is critical for the differentiation of villous CTB cells to a STB phenotype; and we have characterized some of the upstream regulators and downstream targets of AP-21. Our preliminary studies indicate that several extracellular factors that induce CTB cell differentiation stimulate AP-21 expression that the Wnt-beta-catenin- TCF pathway inhibits AP-21 expression during CTB cell differentiation and that AP-21 expression is abnormal in placentas from patients with severe preeclampsia. We now propose a comprehensive investigation into the mechanisms of which AP-21 regulates CTB cell to STB cell differentiation in the context of normal differentiation and in the context of pathologic conditions characterized by abnormal villous CTB differentiation, such as preeclampsia and IUGR. Specific Aim 1 tests the hypothesis that extracellular factors that induce villous CTB differentiation act, at least in part, by an AP-21-dependent mechanism. Aim 2 tests the hypothesis that there is a negative feedback loop between AP-21 and the Wnt-2-catenin pathway and that extracellular factors that induce CTB cell differentiation act at least in part by inhibiting Wnt-2-catenin-TCF signaling. Aim 3 examines the hypothesis that abnormalities in the AP-21 cascade are responsible, at least in part, for the defective villous CTB cell differentiation in preeclampsia and IUGR. The experiments will utilize an in vitro model of human CTB cell differentiation that closely mimics the in vivo differentiation process. The degree of differentiation will be monitored by cell morphology and by the expression of specific STB marker genes. The studies should provide new insights into the molecular mechanisms of placental differentiation and the pathogenesis of the defective placentation in preeclampsia and IUGR. These insights in turn may lead to development of new strategies to treat placental defects that result in fetal morbidity and mortality.