BIOLOGY OF HUMAN TROPHOBLAST DEVELOPMENT

人类滋养细胞发育的生物学

• 批准号: 6272012
• 负责人: LEWIS P RUBIN
• 金额: $ 19.13万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272012
• 关键词: biological signal transduction; calcitonin; cell cycle proteins; cell differentiation; cell fusion; cell growth regulation; cell migration; cyclins; embryogenesis; flow cytometry; gene expression; genetic regulation; hormone regulation /control mechanism; human tissue; interleukin 11; liver cells; myoblasts; northern blottings; nucleic acid sequence; phenotype; prenatal growth disorder; tissue /cell culture; trophoblast; western blottings

Normal human fetal growth and development depend upon a highly regulated cascade of developmental events leading to hemochorial placentation, establishment of uteroplacental contacts and, in late gestation, preparation for perinatal transition. In placenta, the processes of trophoblast proliferation, migration, differentiation, cell fusion and apoptosis are collapsed into the period of gestation. This provides a unique model to study the genes which direct these key maturational events. In addition, abnormal trophoblast differentiation and invasiveness are associated with several common disorders of pregnancy such as intrauterine growth restriction (IUGR), preeclampsia, early pregnancy loss and placenta accreta. We have shown that certain features of human trophoblast differentiation in vivo can be recapitulated in vitro. In preliminary studies we also have uncovered regulatory roles during human trophoblast development for two endogenous polypeptides, the hormone calcitonin and the hormonally-stimulated cytokine interleukin-11 (IL-11). We hypothesize that these factors represent novel physiological modulators of trophoblast differentiation through their actions on trophoblast regulatory genes. We will investigate the effects of these specific factors and their signaling pathways upon trophoblast proliferation, migration and invasiveness, endocrine function and syncytium formation. We also will examine cell cycle regulators involved with differentiation of myoblasts (which also undergo syncytium formation) and hepatocyte cell cycle regulators identified in Subproject I for their effects on trophoblast differentiation. We will identify cell cycle inhibitors and other novel genes differentially regulated during hormone- stimulated trophoblast differentiation. We will isolate and clone these differentially regulated cDNAs and investigate their temporal and cell specific expression during placental development and in pathological samples. The identification of the role of these mechanisms of placental differentiation will provide new pathophysiologic insights into development.

正常的人类胎儿生长和发育取决于高度调节的 级联发育事件导致胎儿胎盘， 建立子宫校的接触，并在妊娠后期建立 准备围产期过渡。 在胎盘中，过程 滋养细胞增殖，迁移，分化，细胞融合和 细胞凋亡塌陷到妊娠期。 这提供了 研究指导这些关键成熟的基因的独特模型 事件。 另外，异常的滋养细胞分化和 侵入性与怀孕的几种常见疾病有关 例如宫内生长限制（IUGR），先兆子痫，早期 妊娠损失和胎盘染色。 我们已经证明了某些功能 可以在 体外。 在初步研究中，我们也发现了调节作用 在人类滋养细胞开发两个内源性多肽的过程中 激素降钙素和激素刺激的细胞因子白介素111 （IL-11）。 我们假设这些因素代表了新型生理 滋养细胞通过其行动的调节剂 滋养细胞调节基因。 我们将研究这些影响 特定因素及其信号传导途径 增殖，迁移和侵入性，内分泌功能和 合成形成。 我们还将检查涉及的细胞周期调节剂 与成肌细胞的区分（也会发生合胞素形成） 和肝细胞细胞周期调节剂在子弹I中确定的 对滋养细胞分化的影响。 我们将确定细胞周期 抑制剂和其他在激素期间受到差异调节的新基因 刺激的滋养细胞分化。 我们将隔离并克隆这些 差异调节的cDNA并研究其时间和细胞 胎盘发育和病理中的特定表达 样品。 鉴定这些胎盘机制的作用 差异化将为新的病理生理学见解 发展。