HIF-1 Alpha Regulation of Trophoblast Differentiation in Vivo

描述(申请人提供)：许多妊娠相关疾病，包括IUGR和先兆子痫，源于胎盘发育异常。在人类和动物模型中的证据表明，从这些怀孕中出生的婴儿在以后的生活中患高血压、心血管疾病、糖尿病和中风的风险增加。据估计，仅在美国，与这些怀孕相关的短期和长期财务成本加起来每年约为70亿美元。重要的是，这些缺陷中的每一种似乎都特定于胎盘中的特定细胞层，这意味着每一种缺陷都与特定的细胞谱系起源有关。例如，早发性IUGR与胎盘营养物质运输细胞缺陷有关，而子痫前期与侵袭性滋养细胞缺陷有关，后者未能重塑母体动脉。以往的研究表明，氧是滋养层细胞分化的重要介质。缺氧诱导因子-1α(HIF-1a)是细胞氧感应机制的重要组成部分，对胎盘形成和胚胎存活至关重要。内源性HIF-1a在低氧(低氧)条件下是活跃的，但在动脉供氧水平时迅速失活，这使得滋养层细胞发生分化。持续的HIF-1a活性抑制培养中的滋养层细胞分化，并与妊娠相关疾病有关。在这项建议中，我们利用新的方法来靶向特定的胎盘细胞系，以研究胎盘HIF-1a在控制滋养层细胞分化中的作用。这项研究将提供新的基因靶向载体，并评估胎盘HIF-1a活性在调节单个滋养层细胞系发育中的重要性，这些滋养层细胞系是胎盘发育和正常胚胎生长所必需的。我们研究计划的长期目标是确定调控滋养细胞分化、胎盘发育、胚胎发育和母体健康的氧信号机制。

DESCRIPTION (provided by applicant): Many pregnancy-associated disorders, including IUGR and pre-eclampsia, stem from abnormal placental development. Evidence in humans as well as animal models suggests that babies born from these pregnancies are at increased risk of hypertension, cardiovascular diseases, diabetes, and stroke later in life. In the US alone, it is estimated that the combined short and long-term financial costs related to these pregnancies are approximately 7 billion dollars per year. Importantly, each of these defects appears to be specific to a particular cell layer in the placenta, implying that each one relates to specific cell lineage origins. For example, early onset IUGR is associated with defects in placental nutrient-transporting cells whereas pre-eclampsia is associated with defects in invasive trophoblast cells that fail to remodel maternal arteries. Previous studies have shown that oxygen is an important mediator of trophoblast differentiation. Hypoxia inducible factor-1 alpha (HIF-1a) is a critical component of the cellular oxygen-sensing machinery and is essential for placental formation and embryonic survival. Endogenous HIF-1a is active under low oxygen (hypoxic) conditions, but becomes rapidly inactivated at arterial levels of oxygen, which allows trophoblast differentiation to occur. Prolonged HIF-1a activity inhibits trophoblast differentiation in culture and is associated with pregnancy- associated disorders. In this proposal, we utilize novel approaches to target specific placental cell lineages in order to investigate the role of placental HIF-1a in controlling trophoblast differentiation. This study will provide novel gene targeting vehicles and evaluate the importance placental HIF-1a activity in regulating the development of the individual trophoblast lineages necessary for appropriate placental development and normal embryonic growth. The long term objective of our research program is to determine the oxygen signaling mechanisms that regulate trophoblast differentiation, placental development, embryogenesis and maternal well being.