HIF-1 Alpha Regulation of Trophoblast Differentiation in Vivo

描述（由申请人提供）：许多妊娠相关疾病，包括IUGR和先兆子痫，源于胎盘发育异常。人类和动物模型的证据表明，这种妊娠方式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更高。据估计，仅在美国，与这些怀孕相关的短期和长期经济成本每年约为70亿美元。重要的是，这些缺陷中的每一个似乎都是特定于胎盘中的特定细胞层的，这意味着每个缺陷都与特定的细胞谱系起源有关。例如，早发性IUGR与胎盘营养转运细胞缺陷有关，而先兆子痫则与侵袭性滋养细胞缺陷有关，而滋养细胞缺陷不能重塑母体动脉。以往的研究表明，氧是滋养细胞分化的重要介质。缺氧诱导因子-1 α (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（缺氧）条件下活跃，但在动脉氧水平下迅速失活，这使得滋养细胞分化发生。HIF-1a活性延长可抑制培养中的滋养细胞分化，并与妊娠相关疾病有关。在本研究中，我们利用新的方法来研究胎盘HIF-1a在控制滋养细胞分化中的作用。本研究将提供新的基因靶向载体，并评估胎盘HIF-1a活性在调节胎盘发育和正常胚胎生长所需的单个滋养细胞谱系发育中的重要性。我们的研究计划的长期目标是确定调节滋养细胞分化，胎盘发育，胚胎发生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. PUBLIC HEALTH RELEVANCE: Normal placental development is essential for any successful pregnancy. Understanding how oxygen sensing regulators control normal placental development will help us understand how pregnancy-associated disorders arise, can be detected, and treated.