Role of miR-210 in placental mitochondrial metabolism

描述(由申请人提供)：不利的宫内环境，在妊娠合并先兆子痫、肥胖或宫内生长受限(IUGR)的情况下出现，为后代在以后的生活中疾病做好准备。胎盘功能调节胎儿的生长和发育，将母体和子宫环境传递给胎儿，并调节胎儿的编程。MicroRNAs(MiRNAs)是一种小的非编码RNA，通过翻译抑制或mRNA降解来调节基因的表达。我们发现miR-210在妊娠合并重度子痫前期或母亲肥胖增加的胎盘中的表达显着增加，但后者仅在女性胎儿存在的情况下表达。这表明miR-210在胎盘对不良宫内环境的反应中起着关键作用，但在肥胖环境中具有性别二型性影响。利用线粒体能量学的新技术，我们描述了子痫前期或肥胖妇女胎盘中显著的线粒体功能障碍，以及初级滋养层细胞miR-210功能的获得和丧失分别导致线粒体活性的丧失或保持。我们最近发现，介导许多炎症反应的转录因子NFkB在母亲肥胖的胎盘中增加，并与mir-210启动子结合，但同样只在女性胎儿的胎盘中。NFkB的行动之前已经被证明是性变态的。这项建议的总体目标是确定miR-210调节线粒体的分子基础，进而调节合并先兆子痫、母亲肥胖或IUGR的妊娠的胎盘功能。中心假设是缺氧、炎症或氧化应激增加miR-210的表达，抑制线粒体呼吸导致胎盘功能障碍。这一假说将通过三个具体目标进行验证：1.确定miR-210在线粒体和胎盘功能中的作用。2.确定NFkB在恶劣条件下介导滋养层细胞miR-210作用的作用；3.鉴定滋养层细胞中新的miR-210靶基因，并确定其在线粒体和胎盘功能中的作用。在所有情况下，我们都将研究效果的性别二形性。这一建议在研究miR-210在正常和不利条件下线粒体和胎盘功能中的作用方面具有创新性。我们将确定缺氧、炎症和氧化应激是否通过调控miR-210表达的转录因子NFkB起作用，识别控制滋养层线粒体功能的新的miR-210靶基因，以及对线粒体功能的操纵是否改变胎盘功能。

DESCRIPTION (provided by applicant): An adverse intrauterine environment, seen in pregnancies complicated by preeclampsia, obesity or intrauterine growth restriction (IUGR), programs the offspring for disease in later life. Placental function regulates fetal growth and development, transducing the maternal and uterine environment to the fetus, and mediating fetal programming. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through translational repression or mRNA degradation. We found significantly increased expression of miR- 210 in placentas from pregnancies complicated by severe preeclampsia or with increased maternal adiposity but the latter only in the presence of a female fetus. This suggests that miR-210 plays a pivotal role in the placental response to an adverse intrauterine environment, but with a sexually dimorphic influence in the obese environment. Using novel technology for measuring mitochondrial energetics, we described significant mitochondrial dysfunction in placentas of preeclamptic or obese women and that gain- and loss-of-function of miR-210 in primary trophoblast resulted in loss or preservation of mitochondrial activity respectively. We have recently shown that the transcription factor NFkB, which mediates many inflammatory responses, is increased in the placenta with maternal adiposity and binds to the mir-210 promoter but again only in the placenta of a female fetus. NFkB action has previously shown to be sexually dimorophic. The overall objective of this proposal is to determine the molecular basis by which miR-210 regulates mitochondrial and in turn, placental function in pregnancies complicated by preeclampsia, maternal obesity or IUGR. The central hypothesis is that hypoxia, inflammation or oxidative stress seen in such pregnancies increase miR-210 expression, which represses mitochondrial respiration causing placental dysfunction. This hypothesis will be tested through three Specific Aims: 1. Determine the role of miR-210 in mitochondrial and placental function. 2. Determine the role of NFkB in mediating the effect of trophoblast miR-210 under adverse conditions, and 3. Identify novel miR-210 target genes in trophoblast and define their role in mitochondrial and placental function. In all cases we will study the sexual dimorphism of effect. This proposal is innovative in studying the role of miR-210 in mitochondrial and placental function in normal and adverse conditions. We will determine if hypoxia, inflammation and oxidative stress act via the transcription factor NFkB governing miR-210 expression, identify novel miR-210 target genes controlling trophoblast mitochondrial function and if manipulation of mitochondrial function alters placental function.