Activation of Human Placental Hormonal Expression

描述（由申请方提供）：胎盘分化的启动代表哺乳动物胚胎发生中最早的事件。胎盘绒毛的滋养层上皮结构的形成对于胎儿-母体单元的生存能力和功能至关重要。滋养层细胞扩增、终末分化和/或功能缺陷是多种产科疾病的基础。胚胎滋养外胚层在发育早期产生两种不同的细胞滋养层谱系：绒毛外细胞滋养层侵入并修饰母体蜕膜以支持生长的胎儿和绒毛合胞体滋养层上皮（STB）。胎盘绒毛的STB层包括胎儿和母体循环之间的界面，并提供营养和气体交换以及建立母体/胎儿激素环境的关键功能。这项资助的目标是确定STB形成和功能的分子事件。我们将使用补充的细胞培养和STB分化的动物模型来关注STB特异性基因激活所涉及的途径。人生长激素基因（hGH）簇的绒毛膜促生长激素（hCS）和生长激素变体（hGH-V）基因的激活将用作STB基因表达的范例。这些基因的表达与STB分化密切相关，到怀孕后半段，这些基因编码母体血清中的主要妊娠激素。重点将放在定义表观遗传途径和染色质修饰导致hCS和hGH-V转录激活。基于这些数据的模型将在离体分化滋养层细胞和转基因小鼠胎盘的发育动态环境中进行测试。提出了四个具体目标：目标一。定义hGH基因簇的表观遗传染色质修饰在区分STB中的进展，目的II。建立STB分化和hCS基因表达之间的联系，目的III。表征P元件在激活hGH簇中胎盘激素表达中的作用，以及目的IV。绘制STB染色质中hGH LCR和hGH簇之间指定胎盘基因激活的长程相互作用。这些研究将有助于了解胎盘的分化和功能，并应有助于在孕产妇和胎儿健康领域的诊断和治疗进展。

DESCRIPTION (provided by applicant): Initiation of placental differentiation represents the earliest event in mammalian embryogenesis. Formation of the trophoblast epithelial structures of the placenta villi is critical to viability and function of the fetal-maternal unit. Defects in trophoblast cell expansion, terminal differentiation, and/or function underlie a wide spectrum of obstetric disorders. Early during development the embryonic trophectoderm gives rise to two distinct cytotrophoblast lineages: extravillous cytotrophoblasts that invade and modify maternal decidua to support the growing fetus and the villous syncytiotrophoblastic epithelium (STB). The STB layer of the placental villi comprises the interface between fetal and maternal circulations and serves the critical functions of nutrient and gas exchange and establishment of a maternal/fetal hormonal environment. The goal of this grant is to define molecular events central to the formation and function of the STB. We will use complementing cell culture and animal models of STB differentiation to focus on the pathway(s) involved in activation of STB-specific genes. Activation of the chorionic somatomammotropins (hCS) and growth hormone variant (hGH-V) genes of the human growth hormone gene (hGH) cluster will be used as paradigms for STB gene expression. Expression of these genes is tightly linked to STB differentiation and by the second half of pregnancy these genes encode the major pregnancy hormones of maternal serum. Emphasis will be placed on defining epigenetic pathways and chromatin modifications leading to hCS and hGH-V transcriptional activation. Models based on these data will be tested in developmentally dynamic settings of ex vivo-differentiating trophoblast cells and in the transgenic mouse placenta. Four Specific Aims are proposed: Aim I. Define the progression of epigenetic chromatin modifications at the hGH gene cluster in differentiating STB, Aim II. Establish linkages between STB differentiation and hCS gene expression, Aim III. Characterize the role of the P-element in activation of placental hormone expression from the hGH cluster, and Aim IV. Map long-range interactions between the hGH LCR and hGH cluster in STB chromatin that specify placental gene activation. These studies will contribute to the understanding of placental differentiation and function and should contribute to diagnostic and therapeutic advances in the field of maternal and fetal health.