Circulating microRNAs as novel regulators of placental and fetal growth in pregnancies complicated by maternal diabetes

Babies born to mothers with diabetes are often bigger than normal. This can be a cause problems for the baby and mother at the time of birth and/or illness in the newborn Studies in mice and in children born to mothers with diabetes have also shown that babies exposed to diabetes in pregnancy have an increased risk of being obese or having diabetes or heart disease when they are older. Currently it isn't known what causes this, but we do know that the placentas from people with diabetes are bigger. During pregnancy molecules known as miRNAs that are present in blood but we have found that some of these including one known as miR-375, are increased in pregnant women with diabetes. We have previously shown that in normal pregnancy, miRNAs help the placenta to grow, so we think that high levels of miR-375 in women with diabetes, might be causing the placenta to grow too big. Other studies have shown that miR-375 is important for the production of insulin and maintaining normal blood sugar levels in adults. We think that these high levels of miR-375 in the mum might also be affecting insulin levels in the babies which is why they are more likely to develop diabetes.

We will use different techniques to investigate how this miRNA regulates growth of the placenta and of the baby. We will then look to see if high levels of this miRNA in the mother's blood affect the health of the baby by measuring blood pressure and assessing whether they are likely to develop diabetes in adulthood. Our studies will use human placentas where possible, however to look at the effect of miRNAs on growth of the baby and to determine if this affects their health in later life, we will need to give miRNAs to the mother and then test the effect. It is currently not possible to do this in humans so we will give miRNAs to pregnant mice and then look at birth weight. We will also look at blood pressure and test whether the offspring develop diabetes in later life.

When we have done these experiments we will know whether miRNAs in mum's blood are causing the placenta and baby to grow bigger and/or if they are responsible for the babies developing diabetes when they are older. If as we suspect, these miRNAs are involved, we should be able to design treatments to reduce these miRNAs in the blood. This will ultimately decrease the short and long term effects of diabetes and reduce the chance of babies developing obesity, cardiovascular disease or diabetes in adulthood.

Macrosomia affects 50% of pregnancies complicated by maternal diabetes. It can cause problems at birth and is associated with an increased risk of developing metabolic complications in adulthood; there are no treatments as the cause is unclear, although it is associated with enhanced placental growth.

microRNAs (miRNAs) regulate placental growth. They are produced within cells but can be released into the circulation to act like hormones. We have shown that levels of a pancreas-derived miR, miR-375, are elevated in pregnant women with diabetes and that miR-375 can enter placenta and cross to the fetus. We now propose that maternal circulating miR-375 contributes to the development of macrosomia by influencing placental growth and/or impacting the future health of the offspring by directly influencing pancreatic development.

In this study we will utilise a combination of ex-vivo human placental tissue and in-vivo rodent models to examine the role of miR-375 in regulating placental development and establish the impact of elevating circulating maternal miR-375 levels on the pre-natal growth and long-term health of the offspring.

The incidence of pregnancy complicated by diabetes is increasing. Identification of new targets for therapeutic intervention may halt the transmission of the disease to the next generation.

The research questions posed within this proposal are of major interest to ACADEMIC GROUPINGS in Biological and BioMedical Sciences. The academic community will benefit from elucidation of novel mechanisms affecting fetal growth complications in pregnancies complicated by diabetes, and the long-term effects of this on the health of the offspring. Examination of the contribution of maternal miRNAs to this, is of fundamental importance as it may lead not only to new ways to predict pregnancies at risk of fetal growth complications, but the development of novel therapeutics to prevent/treat these conditions. As such, research findings will impact greatly on the HEALTH CARE COMMUNITY. We will disseminate findings by publishing primary papers and reviews in high impact journals, and presenting work at national and international meetings. I anticipate that the proposed work will produce 2-3 high-quality primary research papers.

All findings will be of high interest to the GENERAL PUBLIC due to the prevalence of diabetes in our modern society. At its most basic, the work will engage sections of the populous who wish to learn about their health and human physiology. Our research also has realistic potential to inform the general public about how the placenta works, and in turn how important it is for a healthy pregnancy .Our research findings will be delivered to the general public through public engagement activities (e.g. British Endocrine Societies meeting, International Federation of Placenta Associations conference and University of Leeds open days), as well as through mass media.

Benefits of this research to the UK ECONOMY are neither immediate nor guaranteed. However, the incidence of diabetes, particularly in women of reproductive age is growing, and complications arising from diabetes in pregnancy (cardiovascular disease, diabetes in the future generation) are, and will continue to be, a massive burden on the national health care service. This will only increase with the aging population, in which cardiovascular disease and metabolic disturbance is common. Thus, the future economic benefits may be substantial.