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: 8650502
• 负责人: LESLIE MYATT
• 金额: $ 31.02万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650502
• 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 RNA; 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; 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.

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.