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

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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.