Vanderbilt Integrated Center of Excellence in Maternal and Pediatric Precision Therapeutics (VICE-MPRINT)

范德比尔特母婴精准治疗卓越综合中心 (VICE-MPRINT)

• 批准号: 10584236
• 负责人: PRINCE Joseph KANNANKERIL
• 金额: $ 59.32万
• 依托单位: VANDERBILT UNIVERSITY 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: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584236
• 关键词: Address; Adult; Asthma; Attention; Biguanides; Black race; Body mass index; Cesarean section; Childhood; Chronic; Clinical; Clinical Informatics; Conceptions; Coronary heart disease; DNA sequencing; Data; Development; Diabetes Mellitus; Diet; Disease; Elderly; Electronic Medical Records and Genomics Network; Fetal Tissues; Fetal health; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genetic study; Genomics; Gestational Diabetes; Health; Human; Incidence; Individual; Infant; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Life; Maternal Health; Maternal Mortality; Maternal-Fetal Exchange; Mediating; Mediation; Medical; Metformin; Modeling; Morbidity - disease rate; National Institute of Child Health and Human Development; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obesity; Observational Study; Oral; Outcome; Pharmaceutical Preparations; Pharmacological Treatment; Placenta; Placental Biology; Plant Roots; Play; Population; Pre-Eclampsia; Precision therapeutics; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevalence; Publishing; Race; Research; Research Personnel; Research Priority; Risk; Sampling; Shapes; Stroke; Technology; Tissues; United States; United States National Institutes of Health; Vertical Disease Transmission; Woman; biobank; comorbidity; congenital anomaly; cost effective; diabetic; fetal; fetal blood; in utero; indexing; infant outcome; maternal diabetes; maternal obesity; mortality; multidisciplinary; non-diabetic; obesity risk; obstetrical complication; offspring; phenome; pregnant; prepregnancy; prepregnancy obesity; sex; transcriptome; transcriptome sequencing; transmission process

PROJECT SUMMARY In the United States (US), there is a crisis in maternal mortality, which has increased over recent years. The increasing incidence of severe morbidity and mortality tracks with a rising prevalence of chronic health problems such as pre-pregnancy obesity (PPO), which itself is a causal driver of adverse pregnancy outcomes4. Furthermore, observational studies reveal that maternal PPO predicts an offspring’s risks for obesity, coronary heart disease, stroke, type 2 diabetes mellitus (T2D) and asthma. Obesity also increases the risk for obstetric complications, including maternal diabetes, preeclampsia, cesarean delivery, and induced preterm delivery, as well as infant congenital anomalies and macrosomia. In addition, PPO contributes to the “developmental origins of health and disease” (DOHaD), shaping the future health of offspring during childhood and later adult life. Thus, maternal obesity is now a serious maternal and pediatric health crisis. Diabetes is one of the most common comorbidities of PPO, with 1 to 2% of women having type 1 or T2D during pregnancy and another one in five obese women going on to develop gestational diabetes mellitus (GDM). Metformin (an orally used biguanide) to treat diabetes has been shown to have more favorable pregnancy outcomes compared to a controlled diet, however, there is significant debate on its use because metformin crosses the placental barrier and thus may transport into fetal blood. Many medical professionals have preferred insulin or a combination of insulin and oral medications for diabetes treatment during pregnancy due to concerns about the impacts on oral medications on fetal health. Major research gaps we address in this study is include understanding the impact of PPO on placenta gene expression, as well how pharmacologic treatments for comorbidities like diabetes, specifically metformin, further alter expression. This proposal’s premise is rooted in knowledge that mother-to-child transmission of risk for obesity is multifactorial and begins with conception in utero, but understanding the causal mechanisms of risk transmission at play during gestation requires close attention to the maternal-fetal interface. We hypothesize that maternal obesity and metformin used to treat diabetes influence gene transcription in the human placenta in both maternal and fetal tissues. With these Aims we will also establish the Placental Biobank for Genomics and Outcomes (PB-GO), which we propose as a new MPRINT Scientific Core. Our specific aims are: Aim 1. Evaluate associations between placental gene expression, pre-pregnancy BMI. Aim 2. Determine the impact of metformin on placental gene expression. Aim 3. Conduct a phenome-wide association study (PheWAS) in a large clinical population to identify diseases associated with placental gene expression from fetal derived placental tissue. These data will be the basis of a future R01 to deeply assess the impact of maternal health and pharmacologic treatments on placental biology. Furthermore, these data will also be made available via the MPRINT Hub, catalyzing additional studies.

项目概要 在美国，孕产妇死亡率面临着危机，近年来孕产妇死亡率有所上升。 随着慢性病患病率的上升，严重发病率和死亡率不断上升 孕前肥胖（PPO）等问题本身就是不良妊娠的一个诱因 此外，观察性研究表明，母亲的 PPO 可以预测后代的风险。 肥胖、冠心病、中风、2 型糖尿病 (T2D) 和哮喘也会增加。 产科并发症的风险，包括孕产妇糖尿病、先兆子痫、剖宫产和诱导分娩 此外，PPO 还会导致早产、婴儿先天畸形和巨大儿。 “健康与疾病的发育起源”（DOHaD），塑造后代童年时期的未来健康 因此，孕产妇肥胖现在是严重的孕产妇和儿童健康危机。 PPO 最常见的合并症之一，1% 至 2% 的女性在怀孕期间患有 1 型或 T2D 另外五分之一的肥胖女性会患上妊娠期糖尿病 (GDM)。 口服双胍）治疗糖尿病已被证明具有更有利的妊娠结局 然而，与控制饮食相比，其使用存在很大争议，因为二甲双胍跨越了 胎盘屏障，因此可能会转运到胎儿血液中，许多医疗专业人员更喜欢胰岛素或胰岛素。 由于担心妊娠期糖尿病，联合使用胰岛素和口服药物治疗糖尿病 我们在这项研究中解决的主要研究空白包括： 了解 PPO 对胎盘基因表达的影响，以及如何进行药物治疗 糖尿病等合并症，特别是二甲双胍，会进一步改变表达。 肥胖风险的母婴传播是多因素的，并且从受孕开始 子宫内，但了解妊娠期间风险传播的因果机制需要密切关注 我们勇敢地使用二甲双胍来治疗母体肥胖。 糖尿病影响母体和胎儿组织中人类胎盘的基因转录。 我们还将建立胎盘基因组学和结果生物库 (PB-GO)，我们建议将其命名为 我们的具体目标是： 目标 1. 评估胎盘基因之间的关联。 表达，孕前 BMI 目标 2. 确定二甲双胍对胎盘基因表达的影响。 3. 在大量临床人群中进行全表组关联研究（PheWAS）以识别疾病 这些数据将成为与胎儿来源的胎盘组织的胎盘基因表达相关的基础。 未来的 R01 深入评估孕产妇健康和药物治疗对胎盘生物学的影响。 此外，这些数据也将通过 MPRINT 中心提供，从而促进更多研究。