The mechanistic and therapeutic role of circulating microRNA-142 in pregnancies complicated by maternal obesity with fetal cardiac dysfunction

肥胖在想要孩子的女性中越来越普遍。英国是欧洲育龄妇女肥胖率最高的国家。在第一次产前检查时，每7名妇女中就有1人肥胖，每40名妇女中就有1人严重肥胖。肥胖女性比体重健康的女性更容易患上妊娠并发症，如糖尿病、高血压和分娩问题。他们的孩子长得过大，可能在子宫里就有心脏问题，成年后患心脏病的可能性几乎高出30%。目前，还没有治疗方法可以预防母亲肥胖对婴儿的不良影响。我们想要在婴儿出生前识别出导致他们心脏不良变化的生物信使，这样我们就可以在诊所测量或修改它们，提供更好的产妇护理。我们之前发现，一种叫做microRNA-142的分子在肥胖女性新生婴儿的血液中比在健康体重女性新生婴儿的血液中更常见。其他研究表明，肥胖儿童和成人血液中的microRNA-142水平较高，而microRNA-142与儿童的心脏缺陷和高血压有关。在老鼠身上进行的实验表明，心脏中增加的microRNA-142水平会干扰其泵血能力，而阻断microRNA-142则会改善心脏的功能。因此，在肥胖女性中，胎儿血液中高水平的microRNA-142可能像激素一样，导致发育中的心脏发生不利变化。用一种叫做安塔戈米的药物阻断microRNA-142，可能是一种预防肥胖妇女的孩子出现心脏问题的治疗方法。在这个项目中，我们将首先测试新生儿脐带血液中microRNA-142的含量是否与婴儿心脏的超声扫描测量有关。我们将使用已经在NHS妇产医院收集的血液样本进行这些测量。接下来，我们将研究阻断microRNA-142对肥胖怀孕小鼠的影响。我们将用一种能够穿过胎盘到达胎儿的microRNA阻滞剂治疗小鼠，然后用详细的超声波测量胎儿的心脏。最后，我们将通过人类细胞和小鼠实验来评估胎盘本身是否是microRNA-142的来源，以及阻止microRNA从胎盘释放是否会影响胎儿心脏的发育。这个项目有几个潜在的好处。这将帮助我们了解孕妇的肥胖如何导致她们的孩子出现心脏问题，并可能导致预防这些问题的治疗。如果我们证明胎盘会释放microRNA-142，这可能意味着我们可以使用专门针对胎盘的新型药物，以安全的方式修改发送到胎儿心脏的信息，而不会产生副作用。这些发现还可以让我们确定哪些婴儿在出生前或出生前心脏发生不良变化的风险最高，并据此进行治疗。

Obesity is an increasingly common medical condition in women who want to have children. The UK has the highest rates of obesity in women of reproductive age of any country in Europe. At the first antenatal appointment, 1 in 7 women has obesity and 1 in 40 has severe obesity. Women with obesity are more likely than healthy weight women to suffer from pregnancy complications like diabetes, high blood pressure and birth problems. Their babies grow excessively large, can have heart problems in the womb, and are almost 30% more likely to suffer from heart disease when they are adults. Currently, there are no treatments to prevent the adverse effects of maternal obesity on the baby. We want to identify the biological messengers that cause the adverse changes in babies' hearts, before they are born, so that we can measure or modify them in the clinic and provide better maternity care.We previously found that a molecule called microRNA-142 is more common in the blood of new-born babies of women with obesity than in babies of healthy weight women. Other research has shown that blood microRNA-142 levels are high in children and adults with obesity and that microRNA-142 is linked with heart defects and high blood pressure in children. Experiments in mice show that increasing levels of microRNA-142 in the heart interfere with its ability to pump blood, whereas blocking microRNA-142 improves the function of the heart. Therefore, in women with obesity, high levels of microRNA-142 in the blood of the fetus could be acting like a hormone to cause adverse changes in the developing heart. Blocking microRNA-142 with drugs called antagomirs could be a treatment to prevent heart problems in children of women with obesity.In this project, we will first test whether the amount of microRNA-142 in blood from the umbilical cord of new-born babies relates to ultrasound scan measurements of the babies' hearts. We will use blood samples already collected at an NHS maternity hospital for these measurements. Next, we will examine the effect of blocking microRNA-142 in pregnant mice with obesity. We will treat the mice with a type of microRNA blocker that is able to cross the placenta, to the fetus, then measure the heart of the fetus with a detailed ultrasound. Finally, we will evaluate whether the placenta itself is a source of microRNA-142 and whether blocking microRNA release from the placenta affects development of the fetal heart, using experiments in human cells and mice.The project has several potential benefits. It will help us understand how obesity in pregnant women can lead to heart problems in their children and may lead to treatments to prevent them. If we show that the placenta releases microRNA-142, it may mean that we can use new types of drugs that specifically target the placenta, to modify messages sent to the fetal heart in a safe way, without side effects. The findings may also allow us to identify which babies are at highest risk of adverse heart changes, either before or after birth, and to treat them accordingly.