Administrative Supplement to Placental miRNA profiles associated with maternal insulin resistance and fetal adiposity: maternal-placental crosstalk

与母体胰岛素抵抗和胎儿肥胖相关的胎盘 miRNA 谱的行政补充：母体-胎盘串扰

• 批准号: 9911807
• 负责人: Perrie F O'Tierney-Ginn
• 金额: $ 15.69万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911807
• 关键词: Administrative Supplement; Adult; Affect; African American; Birth; Blood; Body Composition; Body mass index; Cesarean section; Childhood; Data; Deposition; Diabetes Mellitus; Ethnic Origin; Fatty acid glycerol esters; Fetal Growth; Fetal Growth Retardation; Gene Expression; Genetic Transcription; Goals; Growth; Heart Diseases; High Risk Woman; Insulin; Insulin Resistance; Lead; Life; Measures; Metabolic; Metabolism; MicroRNAs; Neonatal; Non obese; Not Hispanic or Latino; Obesity; Outcome; Perinatal; Phenotype; Physiology; Placenta; Plasma; Population Heterogeneity; Pregnancy; Pregnancy Outcome; Race; Regulation; Reporting; Risk; Sampling; Schedule; Testing; Thinness; Time; Tissues; Woman; base; biomarker identification; cohort; early pregnancy; experience; fetal; healthy pregnancy; improved; infant adiposity; insulin sensitivity; insulin signaling; maternal obesity; miRNA expression profiling; novel; obesity risk; offspring; prepregnancy obesity; racial disparity; racial diversity; recruit; research study; screening

Project Abstract High adiposity at birth is associated with poor metabolic outcomes and increased risk of obesity in childhood and adult life. Maternal obesity (body mass index >30 kg/m2) is associated with increased fetal adiposity, but not all obese women have obese babies. Non-Hispanic Black or African American women experience a disproportionate amount of pre-pregnancy obesity and fetal growth restriction, in addition to other poor pregnancy outcomes – yet are underrepresented in perinatal research studies investigating the effects of maternal metabolism on fetal growth. Maternal insulin sensitivity is a key predictor of fetal fat accrual, but the mechanisms regulating insulin signaling during pregnancy are unknown. We have found that maternal insulin sensitivity improves 120% following delivery of the placenta, suggesting a placental factor may regulate insulin signaling during pregnancy. As placental growth and gene expression is sensitive to maternal insulin levels in early pregnancy, and correlated to adiposity at birth, we propose that maternal-placental crosstalk is key to fetal growth regulation. Placental-derived microRNAs (miRNA) regulate post-transcriptional gene expression in maternal tissues, and are detectable in maternal plasma throughout pregnancy. Thus, miRNAs may provide both a mechanism for maternal-placental crosstalk, and novel indicators of women at risk of high fetal fat accretion. The overall goal of this supplement is to utilize a well-phenotyped, racially-diverse birth cohort to identify placental miRNA expression profiles associated with alterations in maternal insulin resistance throughout pregnancy resulting in high neonatal adiposity. We hypothesize that placentas of high adiposity infants have a distinctive miRNA expression profile affecting maternal insulin signaling, resulting in high maternal insulin resistance. To test this hypothesis, we will utilize pre-collected samples from our birth cohort. The cohort consists of four groups: lean and obese women who delivered high or low adiposity offspring. These women all had healthy pregnancies, were not diabetic, and recruited at time of scheduled cesarean section where maternal blood, insulin sensitivity data and placental tissue were collected, and neonatal adiposity was measured. This supplemental study will determine whether placental miRNA expression within these four adiposity groups is affected by maternal race/ethnicity, as racial disparities in fetal growth and body composition have been reported. Upon completion of the proposed studies we will have determined: 1) the identity of miRNAs that are associated with high neonatal adiposity in placentas of lean and obese non-Hispanic Black and White women; 2) the relationship between circulating levels of these miRNA and maternal insulin sensitivity at term. Identification of markers of altered placental function affecting neonatal adiposity, detectable non-invasively in pregnancy, will improve our screening for pregnancies at risk of excessive fetal fat accretion and may lead to specific therapies based on the underlying physiology.

项目摘要 出生时高肥胖症与儿童期代谢不良和肥胖风险增加有关 成人生活。母亲肥胖（体重指数>30 kg/m2）与胎儿肥胖增加有关，但 并不是所有的肥胖妇女都有肥胖的婴儿。非西班牙裔黑人或非裔美国妇女经历 不成比例的孕前肥胖和胎儿生长受限，除了其他贫困 妊娠结局-然而，在调查以下因素影响的围产期研究中， 母体代谢对胎儿生长的影响。母体胰岛素敏感性是胎儿脂肪增加的一个关键预测因子，但 妊娠期间调节胰岛素信号传导的机制尚不清楚。我们发现母体胰岛素 胎盘娩出后胰岛素敏感性提高120%，提示胎盘因子可能调节胰岛素 怀孕期间的信号。由于胎盘生长和基因表达对母体胰岛素水平敏感， 早期妊娠，并与出生时肥胖相关，我们提出，母亲-胎盘串扰是关键， 胎儿生长调节胎盘来源的microRNA（miRNA）调节转录后基因表达， 母体组织，并且在整个妊娠期间在母体血浆中可检测到。因此，miRNAs可以提供 这既是母体-胎盘相互作用的机制，也是高胎儿脂肪风险妇女的新指标 增积这种补充的总体目标是利用一个良好的表型，种族多样化的出生队列， 鉴定与母体胰岛素抵抗改变相关的胎盘miRNA表达谱 导致新生儿肥胖率高。我们假设高脂肪胎盘 婴儿具有独特的影响母体胰岛素信号传导的miRNA表达谱， 母体胰岛素抵抗。为了验证这一假设，我们将利用从出生队列中预先收集的样本。 该队列由四组组成：瘦和肥胖的妇女谁提供了高或低肥胖的后代。 这些妇女都有健康的怀孕，没有糖尿病，并在预定的剖宫产时间招募 收集母体血液、胰岛素敏感性数据和胎盘组织的部分，以及新生儿 测量肥胖。这项补充研究将确定胎盘miRNA的表达是否与胎盘中的miRNA表达有关。 这四个肥胖组受母亲种族/民族的影响，因为胎儿生长和身体的种族差异 组合物已被报道。在完成拟议的研究后，我们将确定：1） 在偏瘦和肥胖胎盘中鉴定与高新生儿肥胖相关的miRNAs 非西班牙裔黑人和白色女性; 2）这些miRNA的循环水平之间的关系 和母亲的胰岛素敏感性。影响胎盘功能改变的标志物的鉴定 新生儿肥胖，可在妊娠期无创检测，将改善我们对高危妊娠的筛查 胎儿脂肪过度堆积，并可能导致基于潜在生理学的特定治疗。

项目成果

Placental miRNAs Targeting Cellular Stress Response Pathways Are Highly Expressed in Non-Hispanic Black People.

• DOI: 10.1007/s43032-022-00895-1
• 发表时间: 2022-07
• 期刊: Reproductive sciences (Thousand Oaks, Calif.)