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MRC DiMeN Doctoral Training Partnership: Defining the link between glucose, miRNAs and extracellular vesicles in pregnancies complicated by maternal diabetes

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  • Full or part time
    Prof K.A. Forbes
    Prof E Scott
    Dr N Simpson
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Maternal diabetes currently affects 1 in 20 pregnancies, making it one of the most common obstetric complications, and the incidence is set to rise. The most significant complication of diabetes in pregnancy is pathological fetal growth. Infants born either under- or over-weight are at significantly higher risk of developing cardiometabolic diseases in their adult life. The mechanisms responsible for this are unclear but are linked to altered placental development and function, and to changes in maternal glucose levels. However, whilst maternal hyperglycemia has long been considered the principal determinant of fetal growth complications and the factor most amenable to intervention, the prevalence of pathological fetal growth remains high even in pregnancies that are considered clinically “well controlled”. This suggests that there is a factor other than glucose that is responsible for abnormal fetal growth and/or that current methods for measuring glucose levels fail to detect the variation in glucose levels that is capable of causing altered fetal growth.

Work in our research group has recently shown, using continuous glucose monitoring technology, that temporal changes in maternal glucose levels are linked to altered fetal growth in pregnancies complicated by maternal diabetes. The mechanisms by which these variations in glucose levels. influence fetal growth are unclear, however we have unpublished data showing that (miRNAs) contained in extracellular vesicles (EVs) are also linked to increased fetal growth and that these miRNAs influence placental development. This project will determine (at the molecular and cellular level) how glucose and miRNAs interact to influence placental development and birthweight.

To do this we will recruit pregnant women with diabetes and undertake a detailed two-week period of continuous glucose monitoring (CGM). Maternal blood samples and pregnancy outcome data will be collected, and the following objectives will be addressed:
1) Isolate and characterise EVs and their cargo, from pregnant women with diabetes that deliver infants with pathological fetal growth.
2) Establish the relationship between maternal blood glucose, the transcriptome and proteome of maternal EVs, and fetal growth.
3) Determine the role of maternal EVs and their miRNA/protein cargo on placental development and function.

Techniques and Training
This is a multi-disciplinary project at the interface of basic science and clinical medicine which will be based in LICAMM in the School of Medicine at University of Leeds. The student will have access to world class research facilities and specialist expertise in imaging, molecular biology, sequencing, proteomics and informatics. Specifically, training will be provided in molecular, cellular and extracellular vesicle biology, translational medicine and both wet-lab and in-silico ‘omics’ techniques. Training in patient recruitment, continuous glucose monitoring and the collection of blood and tissue samples will also be provided. The mix of clinicians and scientists within our research team means that the student will be exposed to integrated and synergistic approach to identifying the fundamental biological role of glucose and miRNAs in placental and fetal growth.

Broader impact of the work
By understanding the mechanisms responsible for altered fetal growth, this study could lead to treatments that could ultimately alleviate the complications associated with maternal diabetes and break the generational cycle of diabetes.

Supervisors webpages
Dr Karen Forbes https://medhealth.leeds.ac.uk/profile/500/1346/karen_forbes
Professor Eleanor Scott https://medhealth.leeds.ac.uk/profile/500/379/eleanor_scott
Mr Nigel Simpson https://medhealth.leeds.ac.uk/profile/300/826/nigel_simpson

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: https://goo.gl/8YfJf8
Good luck!

References

Sallam NA, Palmgren VAC, Singh RD, John CM, Thompson JA. Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies. Int J Mol Sci. 2018 19(11).
Law GR, Ellison GTH, Secher AL, Damm P, Mathiesen ER, Temple R, Murphy HR, Scott EM. Analysis of continuous glucose monitoring in pregnant women with diabetes: distinct temporal patterns of glucose associated with large-for-gestational-age infants. Diabetes Care. 2015; 38 (7):1319-1325.

Holder BS, Jones T, Sancho Shimizu V, Rice TF, Donaldson B, Bouqueau M, Forbes KA, Kampmann B. Macrophage exosomes induce placental inflammatory cytokines: a novel mode of maternal-placental messaging. Traffic. 2016; 17 (2):168-178.

Farrokhnia F, Aplin JD, Westwood M, Forbes K. MicroRNA regulation of mitogenic signaling networks in the human placenta. Journal of Biological Chemistry. 2014; 289 (44):30404-30416.



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