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（由申请人提供）：重度子痫前期（sPE）是一种基于胎盘的高血压疾病，影响所有妊娠的2 - 7%。它是全世界胎儿和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的年经济成本为70亿美元。目前，唯一可用的治疗这种疾病是胎盘和胎儿分娩。在严重的情况下，这种疾病会导致早产，而早产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改善重度子痫前期患者的胎盘和母体血管内功能来改善妊娠结局。sPE胎盘的特征在于异常的滋养层分化，其与子宫胎盘灌注减少一起导致缺氧状态，导致异常的胎盘蛋白质分泌，这进而促成母体血管功能障碍、蛋白尿和高血压。最近发现转录因子和核受体过氧化物酶体增殖物激活受体-γ（PPARγ）调节转录因子GCM 1，其调节滋养层分化并在sPE中减少。PPARγ可以通过噻唑烷二酮类药物进行调控，这些药物通常用于治疗II型糖尿病。在大鼠sPE模型中使用罗格列酮，我们已经显示出妊娠结局和母体血管功能的极大改善。我们假设人类滋养层细胞分化受PPARγ-GCM 1轴调节，并且它可以被诱导以改善胎盘，进而改善母体内皮功能。此外，我们挑战目前的原则，病理性蛋白质分泌在先兆子痫主要是由缺氧引起的，而不是建议，它是由异常分化驱动。这一假设将通过完成以下三个具体目标进行严格检验：1。我们将评估PPARγ是否通过直接调节转录因子GCM 1来调节人类滋养层细胞分化，GCM 1是级联反应的一部分，进而调节许多其他蛋白质。2.我们将在sPE的缺氧胎盘外植体模型中测试PPARγ活性的调节是否会改善胎盘功能。3.我们将确定是否可以通过调节PPARγ活性来改变胎盘蛋白分泌以驱动滋养层分化，以及这是否反过来会改善母体内皮功能。将通过在血管生成试验中确定来自用PPARγ活化药物处理的病理组织的培养基是否会改善内皮功能来评估该策略的功效。这项研究的成功完成将解释人类胎盘发育的新途径和先兆子痫的病理生理学。