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

基本信息

批准号：
8448235
负责人：
Theresa L Powell
金额：
$ 25.95万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-20 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448235
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

项目摘要

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.

描述（由申请人提供）：超过 60% 的美国女性在怀孕时体重超重或肥胖，并且胎儿过度生长在这些怀孕中很常见。胎儿过度生长会增加创伤性产伤的风险，并使婴儿在儿童期和以后的生活中容易患上肥胖、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/肥胖女性促炎细胞因子、瘦素和游离脂肪酸 (FFA) 水平的增加会导致胎盘中 TNF-和 IL-6 的释放增加。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，这在体内将导致增加对胎儿的营养输送，并最终促进胎儿生长。为了解决这个模型，我们的中心假设是 FFA 刺激由多种信号通路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 激活，从而促进细胞因子（如 IL-6）的产生。我们进一步提出，由滋养层产生并在母体血浆中循环的细胞因子通过影响特定氨基酸转运蛋白亚型的转录、翻译和/或膜运输来上调滋养层氨基酸转运，部分由STAT3介导。我们将通过三个具体目标来解决这一中心假设： 1. 确定高孕妇体重指数 (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，并将其与母亲 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通路。使用原代人滋养层细胞和 siRNA 技术，我们将描绘出将 FFA 与细胞因子释放增加联系起来的细胞内信号传导途径。 3. 确定促炎细胞因子对胎盘氨基酸转运的影响并确定所涉及的细胞内信号传导机制。我们将采用 siRNA 方法在培养的人原代滋养层细胞中研究关键细胞内信号分子（例如 STAT 3）的作用，并且我们将检查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。拟议的研究具有创新性，因为它们有望确定肥胖引起的母体代谢紊乱与胎盘功能改变之间的机制联系，胎盘功能改变增加了对胎儿的营养输送。这项研究的意义在于，它将提供有关胎儿过度生长的机制的新信息，这可能有助于制定新的干预策略，以减少胎儿过度生长及其短期和长期的健康后果。