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

Lead Research Organisation: University of Leeds
Department Name: School of Medicine

Abstract

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.

Technical Summary

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.

Planned Impact

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.
 
Title Participated in development of MRC NIRG video 
Description This video is aimed at increasing awareness of the MRC New Investigator Research Grant scheme and enhancing the quality of applications. I was featured in the video as was the University of Leeds. 
Type Of Art Film/Video/Animation 
Year Produced 2020 
Impact This will benefit early career researchers and contribute towards the MRC's priority of supporting the next generation of researchers. This will also raise the profile of University of Leeds. 
URL https://www.youtube.com/watch?v=hDR0H14lKXw
 
Description Delivered public engagement training
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Participated in delivery of training in public engagement" 'Introduction to Public Engagement' at University of Leeds, LICAMM Career Development Academy. This is resulted in involvement of early career researchers in several new outreach initiatives aimed at disseminating our research activities to the public locally, nationally & internationally.
 
Description Member of Society for Endocrinology Public Engagement Committee
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL https://www.endocrinology.org/about-us/governance/public-engagement-committee/
 
Description BHF 4 year PhD studentship: EV derived miRNAs as key regulators of placental vascular dysfunction and altered fetal growth in pregnancies complicated by maternal diabetes
Amount £150,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2019 
End 09/2023
 
Description BHF PhD Studentship: Regulation of human cardiac fibroblast function by specific microRNAs
Amount £108,668 (GBP)
Funding ID FS/19/41/34478 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 10/2022
 
Description Genetics Society Summer Studentship (2019)
Amount £2,500 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2019 
End 09/2019
 
Description SfE BES Registration Grant (Katy Walsh)
Amount £500 (GBP)
Organisation Society for Endocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 11/2019
 
Description SfE BES conference travel grant (Margeurite Kennedy)
Amount £600 (GBP)
Organisation Society for Endocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 11/2019
 
Description Society for Endocrinology Travel Award for BES 2019 (Awarded to Karen Forbes)
Amount £600 (GBP)
Organisation Society for Endocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 11/2019
 
Description Society for Endocrinology: - SfE BES conference travel grant
Amount £564 (GBP)
Organisation Society for Endocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 11/2019
 
Description Haiku Crastina Science Competition Prize winner 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Researcher in the group (Katy Walsh) participated in the Crastina Science Haiku Competition. Aimed at disseminating research in a creative way to the public. Katy was received 1st Runner up for her poem to describe her research investigating the impact of maternal glucose on fatal growth:

Blood sugar rising,
My lifeline begins changing
I'm growing, but why?
Year(s) Of Engagement Activity 2019
URL https://crastina.se/science-haiku-2019-announcement
 
Description Letters to a Pre-Scientist 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Letters to a Pre-Scientist (LPS) helps to demystify STEM careers to all students and allows these students to see themselves as scientists in the future. This is achieved by matching a scientist with a student from a high-poverty school, which may not have had any interactions with STEM professionals previously. Once matched, both the scientist and student writes four letters each, over the span of a year. For the scientist, there are themes to apply to the letter, such as "Your career" and "University experience." In addition to writing about your area of research, your letters can include personal details such as hobbies and interests, which helps the student to understand that scientists are just like anyone else.
Letters can also include items, which helps the student to understand your research or what it is like to work at a university, as well as items that may help the student in class, such as earasers and pens. When a class has received all the expected letters, there is a Letter Opening Day in which students share what is written, thus your message is disseminated to the whole class. Additionally, the LPS organisation encourages the scientist to share their letter writing experience via social medial to broaden the impact of the programme on the general public. This activity helps students realise that a career in STEM is achievable regardless of their backgrounds.
Year(s) Of Engagement Activity 2019
URL https://www.prescientist.org
 
Description MRC Zone of I'm a Scientist online engagement 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact The MRC Festival Zone was a four-week-long online event funded by the Medical Research Council (MRC) as part of the MRC Festival of Medical Research. 25 MRC researchers and technical staff put up profiles on the website, and 24 of these engaged with students throughout the month in live CHATs and the ASK section.
1,204 students from 33 schools all over the UK logged in to the zone over the four weeks. 79% of the schools were widening participation and/or underserved, an increase from 59% in 2018's event.
In the ASK section, 342 questions were approved and sent to the researchers and technical staff, who between them wrote 2,072 answers.
63 online live CHATs took place during the event, including four evening CHATs where students could join in from home with their family. An average of six researchers came to each session, giving students a wide variety of roles and people to find out about.
Year(s) Of Engagement Activity 2019
URL http://mrcfestival2019.imascientist.org.uk
 
Description Oral Presentation at UK Extracellular vesicle meeting 2018 (Dr Karen Forbes) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I presented initial findings of our study at UK EV 2019 conference attended by more than 200 delegates. The talk received much interest and has sparked collaborations. I have since been invited by UK Society for Extracellular Vesicle President to set up a regional special interest group for extracellular vesicle research.
Year(s) Of Engagement Activity 2018
 
Description Participation in Society for Reproduction and Fertility Sex in 3 Cities 2020 public outreach event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Had an interactive science stand at Royal Veterinary College's Night at the Vet College as part of the Society for Reproduction and Fertility Sex in 3 cities event (London leg). The event was aimed at public (age 16+) to educate them about reproduction and fertility and the cutting edge of reproduction research.Team volunteers for this included Rachel Quilang, Karen Forbes and Margeurite Kennedy.
Year(s) Of Engagement Activity 2020
URL http://srf-reproduction.org/events/sex-in-three-cities-events/
 
Description Research evening at Pint of Science 2019: 'The Centre of the Womb-iverse' (May 2019) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Pint of Science is a worldwide science festival which brings researchers to their local pub/cafe to present their scientific discoveries. The festival runs over a few days in May every year. I co-ordinated a pregnancy themed evening bringing together scientist and clinicians working in reproductive biology. The event evening was called 'Centre of the womb-verse'. More than 50 members of the public attended and the event was sold out. There were four talks, one of which was delivered by me and an undergraduate student working in my lab. The talk was entitled 'Too much of a sweet thing? Understanding how diabetes in pregnancy impacts birthweight and life-long health of the baby'. The talk sparked much interest with many questions and discussion afterwards. I was approached by patients and members of the public who would like to know more about the research and how they might be able to participate.
Year(s) Of Engagement Activity 2019
URL https://pintofscience.co.uk/event/the-centre-of-the-womb-iverse
 
Description Skype a Scientist - Mrs Yuska's 7th grade class 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Skype a Scientist is an international programme that matches scientists with kindergarten-12th grade classrooms in rural or underfunded schools. The purpose is to put a friendly face to science and lower the intimidation factor that surrounds science for some students.

I did a 60 minute video chat with Mrs Yuska's 7th grade class in Clarksville, Maryland. The teacher asked my to talk to the students about nutrition at a molecular level and to quiz them about what they know about biomolecules.

I talked to them about my research, particularly about how extracellular vesicles can come from food, the body's own cells and that they release nutrients that are being broken down, processed, and used by other cells in the body. These extracellular vesicles and the nutrients are important for health and my research is looking at how they can affect how babies develop and grow. The students were fascinated and ask lots of questions.
Year(s) Of Engagement Activity 2019
URL https://www.skypeascientist.com/for-scientists.html
 
Description Skype a Scientist-Mrs Ranson's fifth grade class 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Skype a Scientist is an international programme aimed at giving students in rural areas and underfunded schools, the opportunity to get to know a "real scientist".

I skyped Mrs Ranson's fifth grade class in Appomattox, VA, USA. After guessing where in the world I am located, I spoke to the students about being a scientist, I talked about some of our work and I showed them some histology slides and what they looked like on the microscope.
The students then asked me questions and there was lots of discussion about science careers, genetics and stem cells.

The teacher reported increased interest in science and the students were excited to learn more about careers in STEM!
Year(s) Of Engagement Activity 2019
URL https://www.skypeascientist.com
 
Description University of Leeds Science Festival: Be Curious 2019 (March 2019) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The purpose of this event was i) to encourage, inspire and enthuse people to access and experience research by providing a positive experience of interactions with staff, activities, equipment and campus facilities; ii) to demonstrate social responsibility by ensuring our research is open and accessible and iii) to provide a high profile platform for researchers from across all faculties to involve and engage with the public, stimulating dialogue and igniting curiosity and trust in research. This transparency and willingness to open doors was aimed at enhancing networks and relationships between researchers and the community.

Be Curious welcomed over 1,200 visitors; 67% were first-timers to Be Curious, and 30% had never visited University of Leeds before. The main reason for attending was 'to entertain my children', followed closely by 'to learn something new'. 27% of guests attending Be Curious were 8 years old and under, which was the second largest demographic. 40-64 year olds made up the largest demographic at 31%. 33% of adults were visitors to the university, 30% staff, 24% alumni and 12% students. 88% of visitors would highly or definitely recommend the event to others.

To specifically engage the public with our research, we developed a stand called "Gestation Station'. The gestation station was aimed at providing an opportunity to see how the womb and the placenta (the organ that connects a mother to her baby) help a baby grow and develop, what can happen if that goes wrong, and how the ground-breaking research being carried out in Leeds is helping to ensure more babies are surviving and living healthy lives. We designed our stall for all the family, and there was a a mix of university staff, clinicians and postgraduate students who were involved in pregnancy research helping at our stand. Our activity had things to do, see and learn including: a 'little lab' for younger children; lots of interactive games activities exploring how the placenta and uterus work; arts and craft for adults and children alike including Play-Doh placentas; discussions
with clinicians on what it is like to work in a pregnancy clinic; and free stickers and tattoos for children. For our specific stand, we had 103 responses to the question ' do you know more about pregnancy research at The University of Leeds? 98% of respondants said that they had gained knowledge.
Year(s) Of Engagement Activity 2019
URL https://twitter.com/hashtag/gestationstation?src=hashtag_click