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 妊娠期间母体胰岛素敏感性的生理性降低是增加营养素的必要条件。 用于胎盘摄取和胎儿分娩。当胰岛素敏感性过度降低时， 在不良妊娠结局中，如妊娠期糖尿病导致巨大胎儿和低血糖， 分娩，以及母亲和后代患糖尿病的长期风险。的调节机制 怀孕期间的胰岛素信号是未知的。母体胰岛素敏感性在几小时内提高120% 这表明胎盘因子可能在妊娠期间调节胰岛素信号。 我们已经确定了胎盘中产生的与母体胰岛素相关的microRNAs（miRNAs） 妊娠晚期敏感指数我们检测到一些胎盘表达的miRNAs， 早在妊娠8-12周时，它们就参与了血液循环，这表明它们可能参与了生理适应。 母亲在怀孕早期开始的葡萄糖代谢。本研究的总体目标是调查 选择的候选胎盘miRNA参与胎盘和胎盘之间相互作用的机制， 妊娠期间的葡萄糖-胰岛素调节。我们假设胎盘中产生的小RNA调节了 通过母体胰岛素，在妊娠期间局部和外周作用以操纵母体胰岛素敏感性。 为了验证这一假设，我们将利用现有的围产期队列，包括纵向前瞻性研究， 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试验， 第一、第二和第三孕期。我们还将利用体外人原代细胞模型， 直接测试胎盘来源的miRNA在局部（胎盘中的旁分泌作用）和胰岛素敏感性 外周组织（内分泌作用）。在完成拟议的研究后，我们将确定：1） 与母体胰岛素敏感性相关的胎盘miRNA对胎盘基因表达的局部影响 2）与母体胰岛素敏感性相关的胎盘miRNA对骨骼肌功能的外周作用， 体外培养的心肌细胞、脂肪细胞和肝细胞; 3）高血糖对胎盘细胞的调节作用 miRNA的表达和释放详细了解这些胎盘的功能和调节 miRNA可能为治疗胰岛素敏感性的病理生理性降低提供新的靶点。