Metformin Effects Placental Trophoblast Function

二甲双胍影响胎盘滋养层功能

• 批准号: 10608822
• 负责人: Amy Miyoshi Valent
• 金额: $ 19.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608822
• 关键词: Admission activity; Adverse effects; Affect; Area; Birth Weight; Blood Glucose; Cell Differentiation process; Cell Proliferation; Cells; Chemicals; Child; Childhood; Clinical Trials; Communication; DNA; DNA Methylation; Data; Diabetes Mellitus; Dose; Drug Exposure; Epigenetic Process; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Fetal Development; Fetal Growth; Fetus; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Gestational Age; Gestational Diabetes; Growth; Growth and Development function; Health; Homeostasis; Hormones; Human Chorionic Gonadotropin; Image; In Vitro; Inflammation; Insulin; Intervention; Knowledge; Life Style Modification; Metabolic; Metabolism; Metformin; Methylation; Mitochondria; Morbidity - disease rate; Morphology; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obesity; Oral; Outcome; Pathway interactions; Perinatal; Pharmaceutical Preparations; Placenta; Placental Hormones; Plasma; Polycystic Ovary Syndrome; Population; Pregnancy; Pregnancy Complications; Production; Publishing; Reporting; Respiration; Risk; Role; Safety; Small for Gestational Age Infant; Syncytiotrophoblast; Testing; Time; United States; Visual; Weight; adverse outcome; blood lipid; body system; cardiometabolism; cell type; comorbidity; cytotrophoblast; epigenomics; fetal; fetal programming; gene function; gestational weight gain; insight; mRNA Expression; neonatal morbidity; offspring; organ growth; peptide hormone; perinatal outcomes; pharmacologic; prenatal exposure; protein expression; transcriptomics; trophoblast; Admission activity; Adverse effects; Affect; Area; Birth Weight; Blood Glucose; Cell Differentiation process; Cell Proliferation; Cells; Chemicals; Child; Childhood; Clinical Trials; Communication; DNA; DNA Methylation; Data; Diabetes Mellitus; Dose; Drug Exposure; Epigenetic Process; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Fetal Development; Fetal Growth; Fetus; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Gestational Age; Gestational Diabetes; Growth; Growth and Development function; Health; Homeostasis; Hormones; Human Chorionic Gonadotropin; Image; In Vitro; Inflammation; Insulin; Intervention; Knowledge; Life Style Modification; Metabolic; Metabolism; Metformin; Methylation; Mitochondria; Morbidity - disease rate; Morphology; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obesity; Oral; Outcome; Pathway interactions; Perinatal; Pharmaceutical Preparations; Placenta; Placental Hormones; Plasma; Polycystic Ovary Syndrome; Population; Pregnancy; Pregnancy Complications; Production; Publishing; Reporting; Respiration; Risk; Role; Safety; Small for Gestational Age Infant; Syncytiotrophoblast; Testing; Time; United States; Visual; Weight; adverse outcome; blood lipid; body system; cardiometabolism; cell type; comorbidity; cytotrophoblast; epigenomics; fetal; fetal programming; gene function; gestational weight gain; insight; mRNA Expression; neonatal morbidity; offspring; organ growth; peptide hormone; perinatal outcomes; pharmacologic; prenatal exposure; protein expression; transcriptomics; trophoblast

PROJECT SUMMARY Optimal fetal growth and development requires robust placental function, which is affected by blood glucose and lipid concentrations but also potentially chemical/drug exposures. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms (transcription activity) that can persist long after exposure to the drug (i.e. pharmacoepigenomics). Our preliminary data has shown differentially methylated regions in DNA from trophoblasts in pregnancies complicated by gestational diabetes (GDM) compared to non-GDM trophoblasts. Moreover, metformin and GDM independently and significantly decreases mitochondrial respiration and placental hormone gene and protein expression in placental trophoblasts. Placental hormones, particularly β- hCG are necessary for normal fetal growth and development. Recent trials using metformin in pregnancy has demonstrated potential maternal benefits such as lower gestational weight gain but higher rates of small-for- gestational age infants and greater weight z-scores and adiposity in children. This highlights the critical gap in our knowledge of the effects of metformin on placental health and its role on potential beneficial and adverse perinatal outcomes. Our objectives are to (Aim 1) determine the effects of metformin on trophoblast epigenomic and transcriptomic profiles and (Aim 2) determine the degree to which metformin treatment suppresses cytotrophoblast maturation and hCG production in GDM and non-GDM placentas. Epigenomic and transcriptomic profiles from isolated trophoblasts in culture for 8-hrs (cytotrophoblasts) and 72-hrs (syncytiotrophoblasts) exposed to metformin will be compared to unexposed trophoblasts from GDM and non- GDM pregnancies. Live cell, time-lapsed imaging throughout trophoblast maturation (8, 24, 48, 72-hrs in vitro culture) will be done to visually correlate morphological maturation with gene markers of trophoblast differentiation and β-hCG production in the presence or absence of metformin cell exposure. Metformin and GDM must be studied together and concurrently because published trial data (i.e. obesity and polycystic ovarian syndrome) has shown they are independently associated with the growth and health of the fetus. We acknowledge metformin has been studied in many organ systems but how it effects the placenta and specifically the trophoblast cells is poorly understood. We believe that it is important to understand the degree to which metformin affects the maturation and metabolism of placental trophoblasts and whether epigenetic mechanisms underlie changes in gene expression patterns that regulate trophoblast function in GDM and non-GDM placentas. This study will offer new information that may caution the use of metformin in pregnancy and set the stage for more refined clinical trials.

项目摘要 最佳的胎儿生长和发育需要鲁棒的占地功能，这受血糖的影响和 脂质浓度，但也可能是化学/药物暴露。药物可能会通过 直接或间接机制（转录活性）可以在暴露于药物后持续很长时间（即 药物毛皮学）。我们的初步数据显示了DNA中不同的甲基化区域 与非GDM滋养细胞相比，妊娠糖尿病（GDM）复杂的妊娠滋养细胞复杂。 此外，二甲双胍和GDM独立并显着下降了线粒体呼吸和 胎盘马酮基因和胎盘滋养细胞中的蛋白质表达。胎盘马，尤其是β- HCG对于正常的胎儿生长和发育是必需的。在怀孕中使用二甲双胍的最新试验具有 表现出潜在的物质益处，例如妊娠体重增加较低，但小小的速度较高 儿童的胎龄婴儿和更大的体重z得分和肥胖。这突出了关键的差距 我们了解二甲双胍对占地健康的影响及其对潜在有益和逆境的作用 围产期结果。我们的目标是（AIM 1）确定二甲双胍对滋养细胞表观基因组的影响 和转录组轮廓和（目标2）确定二甲双胍治疗抑制的程度 GDM和非GDM plecetas中的细胞增生细胞成熟和HCG产生。表观基因组和 来自培养物中分离的滋养细胞的转录组谱，用于8小时（细胞增生细胞）和72小时 （合胞素化质细胞）暴露于二甲双胍的（将其与GDM和非未暴露的滋养层细胞进行比较 GDM怀孕。活细胞，整个滋养细胞成熟（8、24、48、72小时体外）的成像 培养）将进行视觉上的形态成熟与滋养细胞的基因标记 在存在或不存在二甲双胍细胞暴露的情况下，分化和β-HCG产生。二甲双胍和 GDM必须一起研究并同时研究，因为已发布的试验数据（即肥胖和多囊卵巢 综合征）表明它们与胎儿的生长和健康独立相关。我们 确认二甲双胍已经在许多器官系统中研究了 滋养细胞的细胞知之甚少。我们认为了解程度很重要 二甲双胍会影响斑点滋养细胞的成熟和代谢以及是否表观遗传机制 基因表达模式的基础变化，该模式调节GDM和非GDM中的滋养细胞功能 斑点。这项研究将提供新的信息，可能会警告在怀孕中使用二甲双胍，并设置 阶段进行更精致的临床试验。