Maternal pro-inflammatory status in obesity regulates placental function

肥胖中母亲的促炎症状态调节胎盘功能

• 批准号: 8064019
• 负责人: Theresa L Powell
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064019
• 关键词: Address; Adipose tissue; Affect; Age; American; Amino Acid Transport System A; Amino Acid Transporter; Amino Acids; Animal Model; Area; Binding; Biological Markers; Birth; Birth Weight; Birth trauma; Blood; Body mass index; Cell Nucleus; Cell membrane; Cells; Cesarean section; Child; Childhood; Cultured Cells; Data; Development; Diabetes Mellitus; Diabetic mother; Diet; Dyslipidemias; Environment; Epidemic; Epithelial Cells; Epithelium; Evaluation; Evidence based intervention; Fasting; Fatty acid glycerol esters; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gene Silencing; Genetic Transcription; Glucose Intolerance; Goals; Health; High birth weight infant; Hormones; Human; Hyperlipidemia; Hypertension; Inflammatory; Insulin; Interleukin-6; Intervention; Knowledge; Laboratories; Lead; Length; Leptin; Life; Link; Lipids; Literature; Measures; Mediating; Membrane Protein Traffic; Metabolic; Metabolic syndrome; Metabolism; Mitogen-Activated Protein Kinases; Modeling; Mothers; Mus; Nonesterified Fatty Acids; Nuclear; Nutrient; Obesity; Overweight; Perinatal; Peroxisome Proliferator-Activated Receptors; Placenta; Plasma; Play; Pregnancy; Pregnant Women; Process; Production; Protein Isoforms; Proteins; Protocols documentation; Public Health; RNA; Recruitment Activity; Regulation; Regulatory Pathway; Reporting; Research; Risk; Risk Factors; Role; STAT3 gene; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Syncytiotrophoblast; System; TNF gene; Techniques; Technology; Testing; Tissues; Toll-like receptors; Transcriptional Regulation; Translations; Up-Regulation; Woman; adipokines; apical membrane; base; cell type; clinical material; cytokine; design; fetal; fundamental research; high risk; human FRAP1 protein; in vivo; innovation; maternal serum; mother nutrition; next generation; novel; pregnant; public health relevance; reproductive; response; stress-activated protein kinase 1; toll-like receptor 4; transcription factor; translational study; treatment strategy; trophoblast

DESCRIPTION (provided by applicant): More than 60% of American women enter pregnancy overweight or obese and fetal overgrowth is common in these pregnancies. Fetal overgrowth increases the risk for traumatic birth injuries and predisposes the baby for development of obesity, diabetes and hypertension in childhood and later in life. The mechanisms underlying the increased fetal growth in overweight/obese women are largely unknown. Our overall model is that increased levels of pro-inflammatory cytokines, leptin and free fatty acids (FFA) in overweight/obese women cause an increase in TNF- and IL-6 release from the placenta. We propose that these cytokines stimulate amino acid transporter expression and activity, which in vivo will result in increased nutrient delivery to the fetus and ultimately increased fetal growth. To address this model our central hypothesis is that FFA stimulate placental amino acid transport mediated by multiple signaling pathways including binding to Toll Like Receptor 4 resulting in activation of MAP kinase and NF which promotes production of cytokines such as IL-6. We further propose that cytokines, produced by the trophoblast and circulating in maternal plasma, up-regulate trophoblast amino acid transport by affecting transcription, translation and/or membrane trafficking of specific amino acid transporter isoforms, mediated in part by STAT3. We will address this central hypothesis in three specific aims: 1. Determine the impact of high maternal body mass index (BMI) on key intracellular signaling pathways and placental nutrient transport capacity. We will recruit 75 lean, overweight and obese pregnant women and measure expression and activity of key intracellular signaling pathways and nutrient transporters in placenta and correlate these to maternal BMI and metabolic parameters. 2. Establish the effect of FFA on placental cytokine production and define the intracellular signaling pathway mediating the effects. Using primary human trophoblast cells and siRNA techniques, we will delineate the intracellular signaling pathway linking FFA to increased cytokine release. 3. Determine the effect of pro-inflammatory cytokines on placental amino acid transport and identify the intracellular signaling mechanisms involved. The role of key intracellular signaling molecules, such as STAT 3, will be investigated employing siRNA approaches in cultured human primary trophoblast cells, and we will examine three levels of potential regulation of placental amino acid transport capacity: gene transcription, protein translation and membrane trafficking. Our preliminary data give strong support for our central hypothesis. The proposed studies are innovative because they are expected to identify a mechanistic link between the perturbed maternal metabolism in obesity and alterations in placental function, which increases nutrient delivery to the fetus. The significance of this study is that it will provide novel information on the mechanisms underlying fetal overgrowth, which may allow for the development of new intervention strategies in order to reduce fetal overgrowth and its' short- and long-term health consequences. PUBLIC HEALTH RELEVANCE: Overweight and obese women often deliver large babies, which have a high risk to develop obesity, diabetes and hypertension already in childhood. We propose that changes in placental nutrient transport constitutes an important mechanism by which maternal obesity leads to increased birth weight. This is highly relevant to public health since this new information may lead to novel intervention strategies to alleviate fetal overgrowth, which could lessen the epidemic of obesity and diabetes in the next generation.

描述（由申请人提供）：超过60%的美国妇女进入怀孕超重或肥胖和胎儿过度生长是常见的，在这些怀孕。胎儿过度生长增加了创伤性出生损伤的风险，并使婴儿在童年和以后的生活中容易患上肥胖症、糖尿病和高血压。超重/肥胖女性胎儿生长加快的机制在很大程度上尚不清楚。我们的总体模型是，超重/肥胖妇女中促炎细胞因子、瘦素和游离脂肪酸（FFA）水平的增加导致胎盘释放TNF-α和IL-6的增加。我们认为，这些细胞因子刺激氨基酸转运蛋白的表达和活性，在体内将导致增加营养输送到胎儿，并最终增加胎儿的生长。为了解决这个模型，我们的中心假设是FFA刺激由多种信号传导途径介导的胎盘氨基酸转运，包括与Toll样受体4结合，导致MAP激酶和NF活化，从而促进细胞因子的产生， 作为IL-6。我们进一步提出，细胞因子，由滋养层产生的和在母体血浆中循环，通过影响转录，翻译和/或特定的氨基酸转运蛋白亚型的膜运输，上调滋养层氨基酸转运，部分介导的STAT 3。我们将在三个具体目标中解决这个中心假设：1。确定高母体体重指数（BMI）对关键细胞内信号通路和胎盘营养转运能力的影响。我们将招募75名瘦、超重和肥胖孕妇，测量胎盘中关键细胞内信号通路和营养转运蛋白的表达和活性，并将其与母体BMI和代谢参数相关联。2.确定FFA对胎盘细胞因子产生的影响，并确定介导该影响的细胞内信号传导途径。使用原代人滋养层细胞和siRNA技术，我们将描绘连接FFA增加细胞因子释放的细胞内信号通路。3.确定促炎细胞因子对胎盘氨基酸转运的影响，并确定涉及的细胞内信号传导机制。关键的细胞内信号分子，如STAT 3的作用，将采用siRNA方法在培养的人原代滋养层细胞中进行研究，我们将研究胎盘氨基酸转运能力的三个潜在调节水平：基因转录，蛋白质翻译和膜运输。我们的初步数据有力地支持了我们的中心假设。拟议的研究是创新的，因为它们有望确定肥胖中母体代谢紊乱与胎盘功能改变之间的机械联系，这增加了向胎儿提供的营养。这项研究的意义在于，它将提供有关胎儿过度生长机制的新信息，这可能有助于开发新的干预策略，以减少胎儿过度生长及其短期和长期健康后果。 公共卫生关系：超重和肥胖的妇女往往生下大婴儿，这些婴儿在儿童时期就有患肥胖症、糖尿病和高血压的高风险。我们认为胎盘营养转运的变化是母体肥胖导致出生体重增加的重要机制。这与公共卫生高度相关，因为这一新信息可能会导致新的干预策略，以减轻胎儿过度生长，这可能会减少下一代肥胖和糖尿病的流行。