HIF-1 Alpha Regulation of Trophoblast Differentiation in Vivo

HIF-1 Alpha 对体内滋养层分化的调节

• 批准号: 8814119
• 负责人: Thomas L Brown
• 金额: $ 29.71万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814119
• 关键词: Affect; Animal Model; Architecture; Arteries; Automobile Driving; CYP19A1 gene; Cardiovascular Diseases; Cell Differentiation process; Cell Lineage; Cells; Data; Defect; Development; Diabetes Mellitus; Disease; Down-Regulation; Doxycycline; Embryo; Embryonic Development; Failure; Fetal Growth; Fetal Growth Retardation; Financial cost; Future; Gene Targeting; Genes; Giant Cells; Growth; HIF1A gene; Human; Hypertension; Hypoxia; Individual; Labyrinth; Life; Low Birth Weight Infant; Mediator of activation protein; Mus; Nutrient; Oxygen; Placenta; Placentation; Plasmids; Pre-Eclampsia; Pregnancy; Premature Birth; Regulation; Research; Risk; Role; Signal Transduction; Staging; Stroke; Subfamily lentivirinae; Testing; Time; Transgenic Organisms; blastocyst; early onset; embryo/fetus; hypoxia inducible factor 1; in vivo; mutant; novel; novel strategies; offspring; particle; prevent; programs; promoter; public health relevance; stem; trophoblast

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.

描述（由申请人提供）：许多与妊娠相关的疾病，包括IUGR和先兆子痫，源于异常的胎盘发育。人类和动物模型的证据表明，从这些怀孕中出生的婴儿有高血压，心血管疾病，糖尿病和中风的风险增加。仅在美国，据估计，与这些怀孕相关的短期和长期财务成本总计约为每年70亿美元。重要的是，这些缺陷中的每一个似乎都特定于胎盘中的特定细胞层，这意味着每个缺陷都与特定的细胞谱系起源有关。例如，早期发作IUGR与胎盘养分传播细胞的缺陷有关，而前子女前的eClampsia与无法改造母体动脉的侵入性滋养细胞细胞中的缺陷有关。先前的研究表明，氧是滋养细胞分化的重要介体。低氧诱导因子-1α（HIF-1A）是细胞氧气机械的关键成分，对于胎盘形成和胚胎生存至关重要。内源性HIF-1A在低氧（低氧）条件下具有活性，但在氧气水平下迅速灭活，这使得滋养细胞分化发生。长时间的HIF-1A活性抑制了培养中的滋养细胞分化，并且与妊娠相关疾病有关。在此提案中，我们利用新颖的方法来靶向特定的胎盘细胞谱系，以研究胎盘HIF-1A在控制滋养细胞分化中的作用。这项研究将提供新颖的基因靶向车辆，并评估胎盘HIF-1A活性在调节适当胎盘发育和正常胚胎生长所必需的单个滋养细胞谱系的发展中的重要性。我们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传导机制。