Activation of Human Placental Hormonal Expression

人胎盘激素表达的激活

• 批准号: 7097677
• 负责人: NANCY E. COOKE
• 金额: $ 11.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097677
• 关键词: cell differentiation; chromatin; chromatin immunoprecipitation; embryogenesis; gene expression; gene induction /repression; genetic mapping; genetic regulation; genetic transcription; genetically modified animals; hormone regulation /control mechanism; human tissue; laboratory mouse; placenta; pregnancy; somatomammotropin; somatotropin; tissue /cell culture; trophoblast

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.

描述（由申请人提供）：胎盘分化的起始代表哺乳动物胚胎发生中最早的事件。胎盘绒毛滋养层上皮结构的形成对于胎儿-母体单位的生存和功能至关重要。滋养层细胞扩增、终末分化和/或功能的缺陷是多种产科疾病的基础。在发育早期，胚胎滋养外胚层产生两种不同的细胞滋养层谱系：侵入并修改母体蜕膜以支持胎儿生长的绒毛外细胞滋养层和绒毛合体滋养层上皮（STB）。胎盘绒毛的 STB 层构成胎儿和母体循环之间的界面，并发挥营养和气体交换以及母体/胎儿激素环境建立的关键功能。这笔资助的目标是定义对 STB 形成和功能至关重要的分子事件。我们将使用补充 STB 分化的细胞培养和动物模型来重点研究参与 STB 特异性基因激活的途径。人类生长激素基因 (hGH) 簇的绒毛膜生长激素 (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，到妊娠后半期，这些基因编码母体血清中的主要妊娠激素。重点将放在定义导致 hCS 和 hGH-V 转录激活的表观遗传途径和染色质修饰。基于这些数据的模型将在离体分化滋养层细胞的发育动态环境和转基因小鼠胎盘中进行测试。提出了四个具体目标： 目标 I. 定义 hGH 基因簇的表观遗传染色质修饰在分化 STB 中的进展，目标 II。建立 STB 分化和 hCS 基因表达之间的联系，目标 III。描述 P 元件在 hGH 簇胎盘激素表达激活中的作用，以及目标 IV。绘制 STB 染色质中 hGH LCR 和 hGH 簇之间的长程相互作用，指定胎盘基因激活。这些研究将有助于了解胎盘分化和功能，并有助于孕产妇和胎儿健康领域的诊断和治疗进展。