Transcriptional Control of Human Placental Differentiation

描述（由申请方提供）：在人胎盘发育过程中，单核细胞滋养层（CTB）细胞增殖并融合形成合胞体滋养层（STB）表型。虽然这种分化过程对于成功怀孕至关重要，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，已经表明，转录因子AP-21是绒毛CTB细胞分化成STB表型的关键;我们已经表征了AP-21的一些上游调控因子和下游靶点。我们的初步研究表明，诱导CTB细胞分化的几种细胞外因子刺激AP-21的表达，Wnt-β-catenin- TCF途径抑制AP-21在CTB细胞分化过程中的表达，并且AP-21在重度先兆子痫患者的胎盘中表达异常。我们现在提出了一个全面的调查机制，AP-21调节CTB细胞STB细胞分化的正常分化的背景下，并在病理条件的背景下，其特征在于异常绒毛CTB分化，如先兆子痫和IUGR。特异性目的1检验诱导绒毛CTB分化的细胞外因子至少部分通过AP-21依赖性机制起作用的假设。目的2测试AP-21和Wnt-2-连环蛋白通路之间存在负反馈环以及诱导CTB细胞分化的细胞外因子至少部分通过抑制Wnt-2-连环蛋白-TCF信号传导起作用的假设。目的3检验AP-21级联反应的异常至少部分地导致先兆子痫和IUGR中有缺陷的绒毛CTB细胞分化的假设。该实验将利用人CTB细胞分化的体外模型，其密切模拟体内分化过程。通过细胞形态学和特定STB标记基因的表达监测分化程度。这些研究为了解胎盘分化的分子机制以及子痫前期和IUGR中胎盘缺陷的发病机制提供了新的见解。这些见解反过来可能会导致新的策略来治疗导致胎儿发病率和死亡率的胎盘缺陷。 公共卫生相关性：该研究探讨了转录因子AP-21在调节人绒毛细胞滋养层细胞分化为合体滋养层细胞表型中的关键作用。AP-21表达的上游调控和AP-21作用的下游靶点的全面知识将提供关于先兆子痫、宫内生长迟缓和其他妊娠病理条件中胎盘异常的分子病理生理学的重要新信息。

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. PUBLIC HEALTH RELEVANCE: The proposed research examines the critical roles for the transcription factor AP-21 in the regulation of the differentiation of human villous cytotrophoblast cells to a syncytiotrophoblast cell phenotype. A comprehensive knowledge of the upstream regulation of AP-21 expression and the downstream targets of AP-21 action will provide important new information about the molecular pathophysiology of the placental abnormalities in preeclampsia, intrauterine growth retardation and other pathologic conditions of pregnancy.