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

项目摘要 在美国，孕产妇死亡率危机，近年来有所增加。的 严重发病率和死亡率的增加伴随着慢性病患病率的上升 问题，如孕前肥胖（PPO），这本身是一个因果驱动器不良怀孕 结果4.此外，观察性研究表明，母体PPO预测后代的风险， 肥胖、冠心病、中风、2型糖尿病（T2 D）和哮喘。肥胖也会增加 产科并发症的风险，包括产妇糖尿病，先兆子痫，剖宫产，和诱导 早产以及婴儿先天性畸形和巨大儿。此外，PPO有助于 “健康和疾病的发展起源”（DOHaD），在儿童时期塑造后代的未来健康 以及成年后的生活。因此，母亲肥胖症现在是一个严重的孕产妇和儿童健康危机。糖尿病是 PPO最常见的合并症之一，1%至2%的女性在妊娠期间患有1型或T2 D 另外五分之一的肥胖妇女会患上妊娠糖尿病（GDM）。Metalloy（an） 口服双胍）治疗糖尿病的妊娠结局更好 然而，与控制饮食相比，二甲双胍的使用存在很大争议，因为二甲双胍会穿过 胎盘屏障，因此可以运输到胎儿血液中。许多医疗专业人员更喜欢胰岛素或 胰岛素和口服药物的组合用于妊娠期间的糖尿病治疗， 口服药物对胎儿健康的影响。我们在这项研究中解决的主要研究空白包括 了解多酚氧化酶对胎盘基因表达的影响，以及药物治疗对 合并症如糖尿病，特别是二甲双胍，进一步改变表达。这项提议的前提是， 认识到肥胖症风险的母婴传播是多因素的， 子宫内，但了解风险传播的因果机制在妊娠期间发挥作用，需要密切 注意母胎界面。我们假设母亲肥胖和二甲双胍用于治疗 糖尿病影响母体和胎儿组织中人类胎盘中的基因转录。与这些 我们还将建立基因组学和结果胎盘生物库（PB-GO），我们建议将其作为 新的MPRINT科学核心我们的具体目标是：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。目的 3.在大型临床人群中进行全表型关联研究（PheWAS），以识别疾病 与来自胎儿来源的胎盘组织的胎盘基因表达相关。这些数据将是一个 未来R 01深入评估母体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 Hub提供，促进更多的研究。

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.