Activation of human placental hormonal expression

激活人胎盘激素表达

• 批准号: 8109362
• 负责人: NANCY E. COOKE
• 金额: $ 39.75万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109362
• 关键词: Abbreviations; Address; Cardiovascular system; Cell Differentiation process; Cell Line; Cells; Chromatin; Chromatin Structure; Defect; Development; Dominant-Negative Mutation; Epigenetic Process; Epithelial; Fetus; Gases; Gene Activation; Gene Cluster; Gene Expression; Genes; Genetic Variation; Giant Cells; Health; Hormonal; Hormones; Human; Inner Cell Mass; Locus Control Region; Mediating; Modeling; Modification; Molecular Conformation; Mothers; Mus; Nutrient; Pathway interactions; Pituitary Gland; Placenta; Placental Lactogen; Pregnancy; Production; Site; Somatotropin; Somatropin; Source; Stem cells; Syncytiotrophoblast; System; Transgenic Mice; Transgenic Organisms; Variant; chromatin immunoprecipitation; conditioning; cytotrophoblast; embryonic stem cell; fetal; hGH Gene; insight; mouse model; oxygen transport; proto-oncogene protein kfgf; stem cell differentiation; trophoblast

DESCRIPTION (provided by applicant): The earliest known step in mammalian development is the formation of the trophoblast from the totipotential embryonic stem cell. The subsequent differentiation of the trophoblast stem cells (TS) to the placental syncytiotrophoblast (SynT) establishes the epithelial interface between fetal and maternal circulatory systems, mediating essential nutrient exchange and oxygen transport. The SynT also serves as the primary site of fetal hormone production that conditions maternal and fetal systems to sustain a successful gestation. The major hormones synthesized in the SynT are chorionic somatomammotropin (hCS) and growth hormone-variant (hGH-V). Both hormones are encoded in the multi-gene human growth hormone (hGH) gene cluster that also encompasses the pituitary growth hormone gene, hGH-N. We hypothesize that the selective and robust activation of the placental hCS and hGH-V genes during differentiation of TS to SynT reflects a defined progression of epigenetic modifications and alterations in chromatin structures that distinguish this pathway from that involved in activation of hGH-N in pituitary somatotropes. We further hypothesize that this developmental progression reflects global epigenetic controls that are fundamental to SynT differentiation and distinguish this lineage from the TS-derived lineage that leads to the formation of invasive trophoblast cells. The selective activation of the placentally-expressed genes from the hGH cluster thus presents an optimal model for understanding mechanisms of gene activation that underlie TS cell differentiation and that define function(s) of SynT cells in the placenta. Our proposal will address five Specific Aims: I. Establish mouse TS lines that model activation of the hGH locus during SynT differentiation. II. Define the structural alterations at the hGH locus that coincide with SynT-lineage commitment and the subsequent transcriptional induction of the hCS/hGH-V genes. III. Establish mechanistic linkages between SynT differentiation and hGH locus activation. IV. Identify structural features of the hGH locus required for activation in SynT. V. Define higher-order conformations at the hGH chromatin locus in SynT necessary for placenta-specific gene activation. These studies should expand our understanding of placental gene expression and development and expand our insights into the corresponding defects that impact on maternal and fetal health during gestation. PUBLIC HEALTH RELEVANCE: A normally developed and functioning placenta is critical to gestation. It is responsible for essential nutrient exchange and oxygen transport between mother and fetus and is a major source of fetal hormone production. This project will study specific questions regarding the development and function of the human placenta, in some cases using transgenic mouse models. These studies are expected expand our understanding maternal and fetal health during gestation.

描述（由申请人提供）：哺乳动物发育中已知的最早步骤是由全能胚胎干细胞形成滋养层。随后滋养层干细胞 (TS) 分化为胎盘合体滋养层 (SynT)，在胎儿和母体循环系统之间建立上皮界面，介导必需的营养交换和氧气运输。 SynT 也是胎儿激素产生的主要场所，调节母体和胎儿系统以维持成功妊娠。 SynT 合成的主要激素是绒毛膜生长激素（hCS）和生长激素变体（hGH-V）。这两种激素均由多基因人类生长激素 (hGH) 基因簇编码，该基因簇还包含垂体生长激素基因 hGH-N。我们假设，在 TS 分化为 SynT 的过程中，胎盘 hCS 和 hGH-V 基因的选择性和强力激活反映了表观遗传修饰和染色质结构改变的明确进展，从而将该途径与垂体中 hGH-N 激活相关的途径区分开来。生长激素。我们进一步假设这种发育进程反映了对 SynT 分化至关重要的全局表观遗传控制，并将该谱系与导致侵袭性滋养层细胞形成的 TS 衍生谱系区分开来。因此，hGH 簇中胎盘表达基因的选择性激活为理解基因激活机制提供了一个最佳模型，该基因激活机制是 TS 细胞分化的基础，并定义了胎盘中 SynT 细胞的功能。我们的提案将解决五个具体目标： I. 建立小鼠 TS 系，模拟 SynT 分化过程中 hGH 基因座的激活。二.定义与 SynT 谱系承诺一致的 hGH 位点的结构改变以及随后 hCS/hGH-V 基因的转录诱导。三．建立 SynT 分化和 hGH 位点激活之间的机制联系。四．确定 SynT 激活所需的 hGH 位点的结构特征。 V. 定义 SynT 中 hGH 染色质位点的高阶构象，这是胎盘特异性基因激活所必需的。这些研究应该扩大我们对胎盘基因表达和发育的理解，并扩大我们对妊娠期间影响母体和胎儿健康的相应缺陷的认识。公众健康相关性：正常发育和功能正常的胎盘对于妊娠至关重要。它负责母亲和胎儿之间必需的营养物质交换和氧气运输，并且是胎儿激素产生的主要来源。该项目将研究有关人类胎盘发育和功能的具体问题，在某些情况下使用转基因小鼠模型。这些研究有望扩大我们对妊娠期间母婴健康的了解。