The Role of PPARγ in Human Placental Development and Preeclampsia

PPARγ 在人类胎盘发育和先兆子痫中的作用

• 批准号: 8944902
• 负责人: Sascha Drewlo
• 金额: $ 38.22万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8944902
• 关键词: Address; Affect; Angiogenic Proteins; Apoptosis; Binding; Biological Assay; Blood; Blood Vessels; Cessation of life; Chorionic villi; Culture Media; Disease; Endothelial Cells; Endothelium; Foundations; Functional disorder; Gene Silencing; Genes; Genetic Transcription; Goals; Health; Human; Human Development; Hypertension; Hypoxia; In Vitro; Intervention; Link; Maternal Health; Maternal Mortality; Measures; Mediating; Modeling; Molecular Genetics; Mothers; Mus; Neuroglia; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; PPAR gamma; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Physiological; Physiology; Pioglitazone; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy Proteins; Premature Birth; Prolonged Pregnancy; Protein Secretion; Proteins; Proteinuria; Rattus; Regulation; Research; Rodent; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Testing; Thiazolidinediones; Tissues; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Villous; angiogenesis; base; clinically relevant; economic cost; endothelial dysfunction; fetal; genetic approach; heme oxygenase-1; improved; inhibitor/antagonist; maternal morbidity; novel; programs; promoter; protein expression; rosiglitazone; transcription factor; trophoblast

DESCRIPTION (provided by applicant): Severe preeclampsia (sPE) is a placenta-based hypertensive disorder affecting 2 to 7% of all pregnancies. It is the leading cause of fetal and maternal morbidity and mortality worldwide. The Preeclampsia Foundation (2007) estimates the annual economic cost of sPE in the USA to be $7 billion. Presently, the only available cure for this disease is placental and fetal delivery. In severe cases, this disease leads to preterm birth which, in itself, has numerous serious long- term complications. The ultimate goal of this project is to improve pregnancy outcome by ameliorating placental and maternal endovascular function in severe preeclampsia. sPE placentas are characterized by abnormal trophoblast differentiation, which, together with reduced uteroplacental perfusion, results in a hypoxic state leading to abnormal placental secretion of proteins, which in turn contribute to maternal vascular dysfunction, proteinuria and hypertension. The transcription factor and nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARγ), has recently been found to regulate the transcription factor GCM1, which regulates trophoblast differentiation and is reduced in sPE. PPARγ can be manipulated by drugs of the thiazolidinedione class, which are normally used for the treatment of type II diabetes. Using Rosiglitazone in a rat model of sPE, we have shown great improvements in pregnancy outcome and maternal vascular function. We hypothesize that human trophoblast differentiation is regulated by the PPARγ-GCM1 axis and that it can be induced pharmacologically to improve placental and, in turn, maternal endothelial function. Furthermore, we challenge the current tenet that pathological protein secretion in preeclampsia is primarily caused by hypoxia, and suggest instead that it is driven by abnormal differentiation. This hypothesis will be critically tested by completing the following three specifc aims; 1. We will assess whether PPARγ regulates human trophoblast differentiation by direct regulation of the transcription factor GCM1 as part of a cascade that in turn regulates many other proteins. 2. We will test whether modulation of PPARγ activity will improve placental function in a hypoxic placental explant model of sPE. 3. We will determine whether placental protein secretion can be altered through modulation of PPARγ activity to drive trophoblast differentiation, and whether this, in turn, will improve maternal endothelial function. The efficac of this strategy will be assessed by determining in an angiogenesis assay whether media from pathological tissues treated with PPARγ activating drugs will improve endothelial function. Successful completion of this study will explain new pathways in human placental development and the pathophysiology of preeclampsia.

描述（由适用提供）：严重的先兆子痫（SPE）是一种基于胎盘的高血压疾病，影响了所有怀孕的2％至7％。它是全球胎儿和孕产妇发病率和死亡率的主要原因。先兆子痫基金会（2007年）估计，美国SPE的年度经济成本为70亿美元。目前，该疾病的唯一可用治疗方法是占地和胎儿递送。在严重的情况下，这种疾病会导致早产，这本身就有许多严重的长期并发症。该项目的最终目标是通过在严重的先兆子痫中改善占地和母体血管内功能来改善妊娠结局。 SPE斑点的特征是异常的滋养细胞分化，随着子宫牙科灌注的降低，导致蛋白质异常的位置分泌导致蛋白质异常的分泌，进而导致母体血管功能障碍，蛋白尿和高血压。最近发现转录因子和核受体，过氧化物体增生剂激活的受体γ（PPARγ）来调节转录因子GCM1，该因子GCM1调节了滋养细胞的分化并减少了SPE。 PPARγ可以通过噻唑烷二酮类的药物来操纵，通常用于治疗II型糖尿病。在SPE的大鼠模型中，使用Rosiglitazone，我们在妊娠结局和母体血管功能方面有了很大的改善。我们假设人类滋养细胞的分化受PPARγ-GCM1轴的调节，并且可以从物理上诱导它以改善位置，进而将母体内皮功能。此外，我们挑战了当前的宗旨，即先​​兆子痫中的病理蛋白质分泌主要是由缺氧引起的，而是暗示它是由异常分化驱动的。通过完成以下三个特定目的，将对这一假设进行严格检验。 1。我们将评估PPARγ是否通过直接调节转录因子GCM1来调节人类滋养细胞分化，这是级联反过来调节许多其他蛋白质的级联反应。 2。我们将测试PPARγ活性的调节是否会在SPE的低氧斑点外植体模型中提高位置功能。 3。我们将确定是否可以通过调节PPARγ活性来驱动滋养细胞的分化来改变局部蛋白质的分泌，以及这是否会改善母体内皮功能。该策略的有效性将通过在血管生成测定中确定来自PPARγ激活药物治疗的病理组织的培养基是否会改善内皮功能是否会进行评估。这项研究的成功完成将解释人类位置发育中的新途径和先兆子痫的病理生理学。