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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

基本信息

批准号：
10502650
负责人：
Marie-France Hivert
金额：
$ 43.47万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10502650
关键词：
Acute Adipocytes Adipose tissue Blood Circulation Cell model Chromosome 19 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 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 Third Pregnancy Trimester Time Tissues Woman adverse pregnancy outcome 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 targeted treatment uptake

项目摘要

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