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）：妊娠期并发先兆子痫、肥胖或宫内生长受限（IUGR）时出现的不良宫内环境会导致后代在以后的生活中患上疾病。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，并介导胎儿编程。 MicroRNA (miRNA) 是一种小型非编码 RNA，通过翻译抑制或 mRNA 降解来调节基因表达。我们发现，患有严重先兆子痫或母体肥胖增加的妊娠的胎盘中 miR-210 的表达显着增加，但后者仅在女性胎儿存在的情况下。这表明 miR-210 在胎盘对不良宫内环境的反应中发挥着关键作用，但在肥胖环境中具有性别二态性影响。使用测量线粒体能量学的新技术，我们描述了先兆子痫或肥胖女性胎盘中显着的线粒体功能障碍，并且初级滋养层中 miR-210 功能的获得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 在母亲肥胖的胎盘中增加，并与 mir-210 启动子结合，但同样仅在女性胎儿的胎盘中。 NFkB 的作用先前已被证明具有性二态性。该提案的总体目标是确定 miR-210 在患有先兆子痫、母亲肥胖或 IUGR 的妊娠中调节线粒体以及胎盘功能的分子基础。核心假设是，此类妊娠中出现的缺氧、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。该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. 确定 NFkB 在不利条件下介导滋养层 miR-210 作用中的作用，以及 3. 鉴定滋养层中新的 miR-210 靶基因并确定它们在线粒体和胎盘功能中的作用。在所有情况下，我们都将研究效应的性别二态性。该提案在研究 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控制 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 miR-210 靶基因，以及操纵线粒体功能是否会改变胎盘功能。