Endogenous Apelin Receptor Ligands and Early Stages of Preeclamptic Pregnancy

先兆子痫（PE）是一种危及生命的妊娠高血压疾病，发生在所有妊娠的5- 7 例尽管有许多关于PE的研究，但这种疾病没有特定的治疗选择。 了解导致PE的分子因素可以为治疗干预提供基础， 降低这种疾病的发病率，提高母亲和胎儿的存活率，最终导致改善 人民的心血管健康。妊娠期母胎界面的调控机制 导致PE的原因并不明确。爱帕琳能系统，由爱帕琳、爱帕琳（ELA）和爱帕琳 受体（APJ）是一种新型多效性途径，具有治疗PE的靶向潜力。关键初步 数据表明，爱帕琳肽降低血压、蛋白尿并改善子宫胎盘血流动力学， PE大鼠模型。爱帕琳和ELA都作用于爱帕琳受体，并能刺激滋养层功能，然而， Apelin或ELAs对滋养层细胞侵袭作用的分子机制以及 PE中的任一肽是未知的。根据我们发表的和初步的数据，我们假设爱帕琳肽和 胎盘通过对滋养层侵入的刺激作用促进胎盘形成， 丝裂原活化蛋白激酶/细胞外信号调节激酶和microRNA 199信号通路。 我们进一步假设，局部子宫内给予爱帕琳肽或爱帕琳肽可以改善滋养层细胞的生长， 侵犯子宫及胎盘血流动力学，减少PE的发展特点。通过使用 多学科的方法与分子，基因组，生物化学，细胞和生理技术，我们将 建立apelin和ELA的主要形式的生物化学性质，以及 在胎盘和滋养层细胞中的APJ（目的1）;确立apelinergic系统在PE中的治疗潜力 (Aim 2）;并确定导致滋养层细胞增殖的爱帕琳和ELA作用的分子基础 从正常和先兆子痫大鼠胎盘和人胎盘分离的滋养层细胞的原代培养物中的侵袭 滋养层细胞系（Aim 3）。我们的研究将确立apelinergic系统作为一种新的 调节早期妊娠的分子途径，推进了我们对内源性调节的认识。 母胎界面和建立apelinergic系统作为一种新的治疗途径在PE。

Preeclampsia (PE) is a life threatening hypertensive pregnancy disorder that occurs in 5-7% of all pregnancy cases. Despite numerous studies on PE, there are no specific treatment options available for this disorder. Understanding molecular factors that lead to PE could provide a basis for therapeutic interventions that may reduce the incidence of this disease, improve maternal and fetal survival, ultimately leading to improved cardiovascular health of the population. The mechanisms regulating feto-maternal interface during pregnancy leading to PE are not well defined. The apelinergic system, consisting of apelin, elabela (ELA), and the apelin receptor (APJ), is a novel pleiotropic pathway with a potential for therapeutic targeting in PE. Critical preliminary data demonstrate that apelin reduces blood pressure, proteinuria, and improves uteroplacental hemodynamics in PE rat model. Both, apelin and ELA act on apelin receptor and can stimulate trophoblast function, however, the molecular mechanisms of apelin or ELAs actions on trophoblast invasion and the therapeutic potential of either peptide in PE are unknown. Based on our published and preliminary data we hypothesize that apelin and elabela facilitate placentation via stimulatory actions on trophoblast invasion that involve the regulation of mitogen-activated protein kinase/ extracellular signal-regulated kinase and mircoRNA199 signaling pathways. We further hypothesize that the local intrauterine administration of apelin or elabela improves trophoblast invasion and uteroplacental hemodynamics, and reduce the development of PE features. By using multidisciplinary approach with molecular, genomic, biochemical, cellular, and physiological techniques, we will establish the biochemical properties of the major forms of apelin and ELA, and pharmacological properties of APJ in the placenta and trophoblast cells (Aim 1); establish the therapeutic potential of apelinergic system in PE (Aim 2); and determine molecular underpinnings of apelin and ELA actions leading to increased trophoblast cell invasion in primary cultures of trophoblast cells isolated from normal and preeclamptic rat placentas and human trophoblast cell lines (Aim 3). Our studies will establish the significance of the apelinergic system as a novel molecular pathway regulating early pregnancy advancing our knowledge on the endogenous regulation of the feto-maternal interface and establishing the apelinergic system as a novel therapeutic pathway in PE.