Transcriptional Control of Human Placental Differentiation

描述（由申请人提供）：在人胎盘的发育过程中，单核细胞滋养细胞（CTB）细胞增殖并融合形成合胞滋养细胞（STB）表型。尽管这种分化过程对成功怀孕至关重要，但调控这一过程的分子机制尚不清楚。我们的实验室利用人类CTB细胞分化的体外模型，已经表明转录因子AP-21对绒毛CTB细胞向STB表型的分化至关重要；我们已经描述了AP-21的一些上游调节因子和下游目标。我们的初步研究表明，几种诱导CTB细胞分化的细胞外因子刺激AP-21的表达，wnt - β -catenin- TCF通路抑制CTB细胞分化过程中AP-21的表达，严重子痫前期患者胎盘中AP-21的表达异常。我们建议对AP-21在正常分化和以子痫前期、IUGR等异常绒毛状CTB分化为特征的病理条件下调控CTB细胞向STB细胞分化的机制进行全面研究。特异性目的1验证了细胞外因子诱导绒毛CTB分化的假设，至少部分是通过ap -21依赖机制起作用的。Aim 2验证了AP-21与Wnt-2-catenin通路之间存在负反馈回路的假设，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信号传导而起作用。目的3检验了AP-21级联异常至少在一定程度上导致子痫前期和IUGR中绒毛CTB细胞分化缺陷的假设。实验将利用人CTB细胞的体外分化模型，密切模仿体内分化过程。分化程度将通过细胞形态和特定STB标记基因的表达来监测。这些研究将为子痫前期胎盘分化的分子机制以及胎盘缺陷的发病机制和IUGR提供新的见解。这些见解反过来可能导致治疗导致胎儿发病率和死亡率的胎盘缺陷的新策略的发展。

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.