Role of miR-210 in placental mitochondrial metabolism

miR-210在胎盘线粒体代谢中的作用

基本信息

批准号：
9353444
负责人：
LESLIE MYATT
金额：
$ 29.58万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353444
关键词：
Adult 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 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 Thinness Tissues Translational Repression Untranslated RNA Up-Regulation Weight Woman Work adverse pregnancy outcome experimental study extracellular fetal programming improved innovation knock-down loss of function mRNA Transcript Degradation male maternal obesity mitochondrial dysfunction mitochondrial metabolism mutant new technology normotensive novel offspring overexpression p65 programs promoter public health relevance response sexual dimorphism syncytin therapeutic target transcription factor trophoblast

项目摘要

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）：一种不良的宫内环境，在妊娠中出现的妊娠，肥胖或宫内生长限制（IUGR）复杂化，为后来的疾病后代计划。胎盘功能调节胎儿的生长和发育，将母体和子宫环境转化为胎儿，并介导胎儿编程。 microRNA（miRNA）是小型非编码RNA，通过翻译抑制或mRNA降解来调节基因表达。我们发现，由于严重的先兆子痫或孕产妇肥胖的增加，胎盘中miR-210的表达显着增加，而后者仅在女性胎儿存在下。这表明miR-210在胎盘对宫内不良环境的反应中起关键作用，但在肥胖环境中具有性二态影响。我们使用新型技术来测量线粒体能量学，描述了先兆子痫或肥胖女性胎盘中的明显线粒体功能障碍，并在原发性滋养细胞中获得miR-210的功能和功能丧失，分别导致了线粒体活性的损失或保存。我们最近表明，介导许多炎症反应的转录因子NFKB在胎盘中以母体肥胖而增加，并与miR-210启动子结合，但仅在雌性胎儿的胎盘中。 NFKB的作用以前已显示为性二态性。该提案的总体目的是确定miR-210调节线粒体的分子基础，而胎盘功能在妊娠中因先兆子痫，母体肥胖或IUGR而复杂化。中心假设是，这种怀孕中看到的缺氧，炎症或氧化应激会增加miR-210的表达，从而抑制线粒体呼吸，从而导致胎盘功能障碍。该假设将通过三个特定目的进行检验：1。确定miR-210在线粒体和胎盘功能中的作用。 2。确定NFKB在不利条件下介导滋养细胞miR-210的作用中的作用，3。确定新型的miR-210靶基因在滋养层细胞中的作用，并定义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二态性。该建议在研究miR-210在正常和不利条件下的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控制miR-210表达的转录因子NFKB，确定控制滋养细胞线粒体功能的新型miR-210靶基因以及线粒体功能的操纵改变了胎盘功能。