Gestational diabetes pathophysiology uncovered by placental transcriptomics

胎盘转录组学揭示妊娠糖尿病病理生理学

• 批准号: 10200103
• 负责人: Marie-France Hivert
• 金额: $ 68.02万
• 依托单位: HARVARD PILGRIM HEALTH CARE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200103
• 关键词: Adipocytes; Anthropometry; Beta Cell; Bioinformatics; Biological Assay; Biological Markers; Blood specimen; Cell model; Cell physiology; Cellular Assay; Classification; Communities; Defect; Development; Diabetes Mellitus; Diagnosis; Endocrine; Ensure; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Face; Fasting; First Pregnancy Trimester; Functional disorder; Genetic; Genotype-Tissue Expression Project; Gestational Diabetes; Glucose; Growth; High Risk Woman; Human; Hyperglycemia; In Vitro; Incidence; Insulin; Lead; Mass Spectrum Analysis; Measurement; Measures; Metabolic Diseases; Methods; MicroRNAs; Modeling; Mothers; OGTT; Pharmacological Treatment; Phenotype; Physiological; Physiology; Placenta; Placental Hormones; Plasma; Population; Pregnancy; Pregnancy Proteins; Pregnant Women; Procedures; Process; Prospective cohort; Prospective cohort study; Proteins; Quantitative Reverse Transcriptase PCR; RNA; Regulation; Reproducibility; Research Personnel; Risk; Risk Factors; Role; Sampling; Second Pregnancy Trimester; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcript; Translating; United States National Institutes of Health; Woman; assay development; base; blood glucose regulation; circulating microRNA; clinical risk; cohort; early detection biomarkers; early pregnancy; enhancing factor; euglycemia; experience; experimental study; genome-wide; glucose metabolism; glucose uptake; high risk population; in vitro Assay; in vivo; indexing; insulin secretion; insulin sensitivity; miRNA expression profiling; multi-ethnic; novel; novel therapeutics; offspring; population based; predictive marker; pregnancy disorder; preservation; prospective; protective factors; response; therapeutic development; therapeutic target; therapy development; transcriptome sequencing; transcriptomics

Summary abstract During pregnancy, women experience major physiologic changes in glucose regulation that are regulated by the placenta. In some pregnant women, regulation between insulin sensitivity and secretion is imbalanced, leading to gestational diabetes mellitus (GDM). GDM is the most common metabolic disorder in pregnancy and leads to complications in both mothers and offspring during pregnancy and long afterwards. Better understanding of the placental role in gestational glucose regulation is necessary to identify early biomarkers that predict GDM, and for the development of novel therapeutic agents to influence insulin secretion and insulin sensitivity, the two major pathophysiologic determinants of diabetes inside and outside of pregnancy.. We propose to conduct placental genome-wide transcriptomic studies using the most recent methods for RNA- sequencing and cutting-edge technology for miRNA sequencing. Placenta samples (n=662) were carefully collected in a population-based prospective cohort of pregnant women called Gen3G. We have collected refined phenotypes and plasma samples in 809 Gen3G women across gestation, including oral glucose tolerance tests allowing us to characterize their insulin secretion, insulin sensitivity, and objectively diagnosed GDM. For identified miRNA associated with insulin secretion in vivo, we will test whether they can stimulate insulin secretion in in vitro validated β-cell models. For identified miRNA associated with insulin sensitivity, we will test whether they can influence glucose-uptake in in vitro adipocytes models. After meticulous selection of the most promising transcripts from our GDM vs normoglycemic women, we will develop assays to detect secreted proteins in maternal plasma collected at 1st trimester. We will test associations between newly identified placenta-specific secreted proteins (ELISA or Mass Spectrometry) and miRNA (RT-qPCR) detectable in plasma at 1st trimester with GDM incidence. We will replicate our findings in two prospective multi-ethnic cohorts of pregnant women. This proposal leverages the richness of the unique Gen3G cohort, including placenta samples carefully collected and preserved for transcriptomic studies, refined phenotypes of glucose regulation and plasma samples across gestation. The team of investigators assembled for this application has substantial expertise and previous experience to conduct each step of the proposed study. Finally, our transcriptomic results will be rapidly available to the wider scientific community on the highly accessed GTEx portal, as we will follow all their standard procedures for our sequencing.

摘要摘要 怀孕期间，妇女在葡萄糖调节中经历了重大生理变化 lopeta。在某些孕妇中，胰岛素敏感性和分泌之间的调节是不平衡的， 导致妊娠糖尿病（GDM）。 GDM是怀孕和 在怀孕期间和之后很长一段时间内导致母亲和后代的并发症。更好的 必须了解妊娠葡萄糖调节中胎盘作用以识别早期生物标志物 这可以预测GDM，并为了开发新型热剂来影响胰岛素分泌和胰岛素 敏感性，妊娠内外糖尿病的两个主要病理生理决定剂。 我们建议使用最新的RNA- miRNA测序的测序和尖端技术。仔细的斑点样品（n = 662） 收集在一个名为GEN3G的孕妇的前瞻性孕妇中。我们已经收集了 809 Gen3g妇女的精制表型和等离子体样品，包括口服葡萄糖 耐受性测试使我们能够表征其胰岛素分泌，胰岛素敏感性和客观诊断 GDM。对于与体内胰岛素分泌相关的已鉴定的miRNA，我们将测试它们是否可以刺激 体外验证的β细胞模型中的胰岛素分泌。对于与胰岛素敏感性相关的已鉴定的miRNA，我们 将测试它们是否可以影响体外脂肪细胞模型中的葡萄糖摄取。精心选择后 我们的GDM与正常血糖妇女的最有希望的成绩单，我们将开发Assas来检测 在三个月收集的Mater血浆中的分泌蛋白质。我们将测试新近之间的关联 可检测的可检测到的斑点特异性分泌蛋白（ELISA或质谱法）和miRNA（RT-QPCR） 在第1个孕期的血浆中，带有GDM事件。我们将在两个潜在的多种族中复制我们的发现 孕妇的同伙。 该提案利用了独特的Gen3G队列的丰富性，包括placeta样品 收集并保存用于转录组学研究，葡萄糖调节和血浆的精制表型 样品跨妊娠。为此申请组装的调查人员团队具有丰富的专业知识 以及先前进行拟议研究的每个步骤的经验。最后，我们的转录组结果将是 在高度访问的GTEX门户网站上，更广泛的科学界迅速可用，因为我们将遵循他们的所有 我们测序的标准程序。