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(MRC DTP) Placental vascular development in pregnancies complicated by diabetes

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  • Full or part time
    Dr J Myers
    Dr E Johnstone
    Dr P Brownbill
    Dr I Chernyaysky
  • 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 (type 1 & 2) complicates 2-3% of pregnancies. Abnormal fetal growth is common in these pregnancies, manifest as both fetal overgrowth (macrosomia) and fetal growth restriction. As a result, catastrophic pregnancy outcomes such as stillbirth are five times higher in women with diabetes. Furthermore, the children of mothers with diabetes in pregnancy who are born under or over weight are three times more likely to be affected by obesity, diabetes and cardiovascular disease as adults. Maternal glycaemic control is known to be one of the major drivers of fetal growth, but recent work by our group has demonstrated that glycaemia also significant affects vascular development in the placenta and may contribute to a significant placental function to fetal growth mismatch, increasing the likelihood of stillbirth and neonatal complications. In this project we will test the hypothesis that suboptimal maternal glycaemic control leads to abnormal vascular development and placental dysfunction. We will also investigate the possible mediators of abnormal vascular development including glucose± insulin/metformin, advanced glycation end products and oxidative stress which have all been implicated in abnormal vessel formation in other vascular beds in diabetes. We have ongoing funding and an established clinical research team who collect continuous glucose monitoring data and measure longitudinal fetal growth and placental function throughout gestation in women with and without diabetes. Clinical data will be paired with ex vivo analysis of placental vascular structure using placental casting and high-resolution imaging with a micro-CT – technique established in our group. This technique enables the analysis of the placental vascular structure in relation to in vivo assessments of placental function1,2. In addition, we have established a collaboration with Dr Caitlin Wyrwoll (University of Western Australia) who is developing novel analytical techniques to quantify the branching structure and model the haemodynamics of complex vascular structures in animal placentas3. The opportunity to work with Dr Wyrwoll’s team developing these novel techniques in human placentas will be an integral part of this PhD project. We have also established a model of in vitro angiogenesis coupled to time-lapsed imaging methods using endothelial cells exposed to altered glucose, insulin and concentrations. In this project we will develop this in vitro method further using placental microvascular endothelial cells, isolated from placentas with and without diabetes, to investigate the signalling mechanisms by which maternal diabetes leads to abnormal placental vascular development and function (e.g. altered glucose, altered angiogenic signalling, AGEs).

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Erlich A, Pearce P, Mayo RP, Jensen OE & Chernyavsky IL (2019) Science Advances 5:eaav6326 (http://doi.org/10.1126/sciadv.aav6326).

2. Erlich A, Nye GA, Brownbill P, Jensen OE & Chernyavsky IL (2019) Interface Focus 9:20190021 (http://doi.org/10.1098/rsfs.2019.0021).

3. Bappoo N, Kelsey LJ, Parker L, et al. (2017) Biomech Model Mechanobiol 16:1361 (https://doi.org.10.1007/s10237-017-0892-8).



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