Role of miR-210 in placental mitochondrial metabolism

miR-210在胎盘线粒体代谢中的作用

• 批准号: 8895208
• 负责人: LESLIE MYATT
• 金额: $ 6.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895208
• 关键词: Adult; Adverse effects; Affect; Amino Acid Transporter; Anti-Inflammatory Agents; Antioxidants; Binding; Biogenesis; Biological Preservation; Cell Death; Cells; Cellular Stress; DNA; Data; Disease; Elderly; Environment; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression; Gene Targeting; Genes; Genus Hippocampus; Health; Hormones; Human; Human Chorionic Gonadotropin; Hypoxia; Inflammation; Inflammatory; Inflammatory Response; Life; Link; Measures; Mediating; Messenger RNA; Metabolism; Methods; MicroRNAs; Mitochondria; Molecular; Obesity; Overweight; Oxidative Stress; Pathway interactions; Placenta; Play; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Production; Proteins; Publishing; Reactive Oxygen Species; Regulation; Reporting; Respiration; Reverse Transcriptase Polymerase Chain Reaction; Role; Specificity; Stress; Sulofenur; Testing; Tissues; Translational Repression; Untranslated RNA; Up-Regulation; Weight; Woman; Work; base; extracellular; fetal programming; improved; innovation; loss of function; mRNA Transcript Degradation; male; mitochondrial dysfunction; mutant; new technology; normotensive; novel; offspring; overexpression; p65; programs; promoter; public health relevance; research study; response; sexual dimorphism; syncytin; therapeutic target; transcription factor; trophoblast

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.

描述（由申请人提供）：不良的宫内环境，见于妊娠合并先兆子痫，肥胖或宫内生长受限（IUGR），使后代在以后的生活中有疾病。胎盘功能调节胎儿的生长发育，将母体和子宫环境传递给胎儿，并介导胎儿程序设计。MicroRNAs （miRNAs）是一种小的非编码rna，通过翻译抑制或mRNA降解来调节基因表达。我们发现miR- 210在伴有严重先兆子痫或母体肥胖的孕妇胎盘中的表达显著增加，但后者仅在女性胎儿存在时才会增加。这表明miR-210在胎盘对不良宫内环境的反应中起关键作用，但在肥胖环境中具有性别二态影响。利用测量线粒体能量的新技术，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，以及初级滋养细胞中miR-210功能的增加和丧失分别导致线粒体活性的丧失或保留。我们最近发现介导许多炎症反应的转录因子NFkB在母体肥胖的胎盘中增加，并与mir-210启动子结合，但同样仅在女性胎儿的胎盘中。NFkB的作用以前被证明是两性二异形的。本提案的总体目标是确定miR-210调节线粒体的分子基础，进而调节伴有先兆子痫、产妇肥胖或IUGR的妊娠中胎盘功能。核心假设是，这种妊娠中出现的缺氧、炎症或氧化应激会增加miR-210的表达，从而抑制线粒体呼吸，导致胎盘功能障碍。这一假设将通过三个具体目标进行检验：1。确定miR-210在线粒体和胎盘功能中的作用。2. 2 .确定NFkB在逆境条件下介导滋养细胞miR-210的作用；在滋养细胞中鉴定新的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，我们将研究效应的两性二态性。该提议在研究miR-210在正常和不良条件下对线粒体和胎盘功能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，确定控制滋养层线粒体功能的新型miR-210靶基因，以及线粒体功能的操纵是否会改变胎盘功能。