Placental miRNAs paracrine and endocrine roles in insulin sensitivity in pregnancy

胎盘 miRNA 旁分泌和内分泌在妊娠期胰岛素敏感性中的作用

• 批准号: 10684929
• 负责人: Marie-France Hivert
• 金额: $ 40.16万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684929
• 关键词: Acute; Adipocytes; Adipose tissue; Cell model; Chromosome 19; Circulation; DNA Methylation; Data; Development; Diabetes Mellitus; Endocrine; Endocrinology; Epigenetic Process; Exposure to; Fatty Acids; Fetal Growth; Fetal Macrosomia; First Pregnancy Trimester; Functional disorder; Gene Expression; Genes; Gestational Diabetes; Glucose; Glucose tolerance test; Goals; Hepatocyte; Hour; Human; Hyperglycemia; Hypoglycemia; In Vitro; Insulin; Intervention; Late pregnancy; Leptin; Liver; Measures; Metabolic; MicroRNAs; Modeling; Mothers; Muscle; Muscle Cells; Muscle Fibers; Nutrient; Nutrient availability; OGTT; Oral; Pathway interactions; Perinatal; Peripheral; Phenotype; Physiological; Physiological Adaptation; Physiology; Placenta; Placental Biology; Plasma; Play; Pregnancy; Pregnancy Outcome; Production; Prospective cohort; Proteins; Regulation; Risk; Role; Sampling; Second Pregnancy Trimester; Site; Somatomedins; Testing; Therapeutic Agents; Third Pregnancy Trimester; Time; Tissues; Woman; adverse pregnancy outcome; candidate selection; circulating microRNA; cohort; early pregnancy; experimental study; fetal; gene function; genome wide association study; glucose metabolism; glucose uptake; improved; indexing; insulin regulation; insulin sensitivity; insulin signaling; interest; maternal hyperglycemia; member; novel; novel therapeutics; offspring; paracrine; prospective; response; small molecule; uptake

Project Abstract The physiological decrease in maternal insulin sensitivity during pregnancy is necessary to increase nutrient availability for placental uptake and fetal delivery. When the decrease in insulin sensitivity is excessive, it results in adverse pregnancy outcomes such as gestational diabetes leading to fetal macrosomia and hypoglycemia at delivery, and long-term risk for development of diabetes in mother and offspring. The mechanisms regulating insulin signaling during pregnancy are unknown. Maternal insulin sensitivity improves 120% within hours following delivery of the placenta, suggesting a placental factor may regulate insulin signaling during pregnancy. We have identified microRNAs (miRNAs) produced in the placenta that are associated with maternal insulin sensitivity index in late pregnancy. We detected some of these placenta-expressed miRNAs in maternal circulation as early as 8-12 weeks of gestation, suggesting they may be involved in the physiological adaptations of maternal glucose metabolism beginning early in pregnancy. The overall goal of this study is to investigate mechanisms by which selected candidate placental miRNA participate in the interplay between placenta and glucose-insulin regulation during pregnancy. We hypothesize that miRNA produced in the placenta and regulated by maternal glycemia, act locally and peripherally to manipulate maternal insulin sensitivity during pregnancy. To test this hypothesis, we will leverage our existing perinatal cohorts which include longitudinal prospectively collected plasma samples and insulin sensitivity index (ISI) data derived from oral glucose tolerance tests in the first, second and third trimesters of pregnancy. We will also utilize in vitro human primary cellular models to directly test the function of placenta-derived miRNA locally (paracrine actions in placenta) and in insulin-sensitive peripheral tissues (endocrine actions). Upon completion of the proposed studies we will have determined: 1) the local effect of placental miRNA related to maternal insulin sensitivity on placental gene expression and function; 2) the peripheral effect of placental miRNA related to maternal insulin sensitivity on skeletal myocytes, adipocytes and hepatocytes in vitro; 3) the regulatory role of hyperglycemia on placental miRNA expression and release. A detailed understanding of the function and regulation of these placental miRNA may provide us with novel targets for treatment of pathophysiological decreases in insulin sensitivity.

项目摘要 怀孕期间孕产妇胰岛素敏感性的生理降低是为了增加养分 胎盘摄取和胎儿分娩的可用性。当胰岛素敏感性的降低过高时，它会导致 在不良妊娠结局中，例如妊娠糖尿病，导致胎儿大疾病和低血糖 分娩以及母亲和后代糖尿病的长期风险。调节的机制 怀孕期间的胰岛素信号传导尚不清楚。母体胰岛素敏感性在几个小时内提高了120％ 胎盘递送后，提示胎盘因子可能会调节怀孕期间的胰岛素信号传导。 我们已经鉴定出与母体胰岛素相关的胎盘中产生的microRNA（miRNA） 怀孕晚期的敏感性指数。我们在母体中检测到其中一些表达的胎盘表达的miRNA 妊娠的循环早在8-12周，这表明它们可能参与了生理适应 孕产妇葡萄糖代谢从怀孕开始。这项研究的总体目标是调查 选定候选胎盘miRNA的机制参与了胎盘和之间的相互作用 怀孕期间的葡萄糖 - 胰岛素调节。我们假设miRNA在胎盘中产生并调节 通过母体血糖，在本地和周围起作用，以在怀孕期间操纵母体胰岛素敏感性。 为了检验这一假设，我们将利用我们现有的围产期队列，包括纵向 收集的血浆样品和胰岛素敏感性指数（ISI）数据来自口服葡萄糖耐量测试的数据 第一，第二和第三孕期怀孕。我们还将利用体外人类主要细胞模型 直接测试局部胎盘衍生的miRNA（胎盘中的旁分泌作用）和胰岛素敏感的功能 周围组织（内分泌作用）。拟议的研究完成后，我们将确定：1） 胎盘miRNA与母体胰岛素敏感性有关的局部影响对胎盘基因表达和 功能; 2）与母体胰岛素敏感性有关的胎盘miRNA对骨骼的外围作用 体外心肌细胞，脂肪细胞和肝细胞； 3）高血糖在胎盘上的调节作用 miRNA表达和释放。对这些胎盘功能和调节的详细理解 miRNA可以为我们提供用于治疗胰岛素敏感性病理生理降低的新靶标。