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(MRC CASE) Integrated in vitro and in silico microphysiological human placental barrier models for reproductive toxicology testing in the pharmaceutical industry


Faculty of Biology, Medicine and Health

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Dr P Brownbill , Dr Peter Ruane , Dr I Chernyaysky No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The pharmaceutical industry has a pressing challenge of providing additional advice on the safety of prescription medicines in pregnancy and how ex vivo and in vitro human placental models might be advanced to reproducible human placental test systems (HPTSs), refining a weight of evidence to the guidance given around compound risk assessment during pregnancy [1]. However, all toxicity testing (in vivo, in vitro and in silico) have limitations when extrapolating from animals to the human, or even from cell/tissue to whole organism. Given new ICH S5 revision 3 guidelines on animal use, new in vitro and in silico approaches are needed to improve the evidential value of data alongside other assays; and to build a bigger picture for risk assessment of compounds passing through the testing pipeline in the pharmaceutical industry. Increasing screenability of test compounds within new test systems as well as to demonstrating the robustness of the models is key.
This interdisciplinary PhD program addresses a pressing challenge via the development, evaluation and standardisation of a human “placenta on a chip” HPTS, advanced towards a regulated level for use by the pharmaceutical industry to acquire reliable transfer data of test compounds from the maternal to the fetal circulatory systems. The project will appeal to a bioengineering student interested in developing a synthetic human placental barrier and modelling [2] the transmembrane transfer of compounds in an academic and industrial environment. Human primary stem cell trophoblasts [3], forming a true syncytiotrophoblast barrier [4] will be co-cultured with human placental endothelial cells to form a differentiated and polarised placental barrier between opposing maternal and fetal circulatory-phase compartments. Barrier compound clearance studies will be compared to ex vivo data from the human placental dual perfusion model; in vivo animal data; and to known human fetal:maternal plasma ratios for drugs already prescribed in pregnancy. The physical properties of the barrier, including length of diffusional pathway, porosity and fetal-side (acceptor-side) flow will be mathematically modelled for transfer efficacy and tested in the developed barrier system.
The candidate will be expected to work flexibly at all locations to develop skills within the Maternal & Fetal Health Research Centre at St Mary’s Hospital (supervised by Drs Paul Brownbill and Peter Ruane) and the Department of Mathematics (supervised by Dr Igor Chernyavsky) at the University of Manchester; and the Clinical Pharmacology and Safety Sciences Team at AstraZeneca, Cambridge (supervised by Drs Nicola Powles-Glover and Rhiannon David).

https://www.research.manchester.ac.uk/portal/paul.brownbill.html
https://www.research.manchester.ac.uk/portal/peter.ruane.html
https://www.research.manchester.ac.uk/portal/igor.chernyavsky.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/) .
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/


Funding Notes

This is a CASE studentship in partnership with AstraZeneca.. Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References


1. P. Brownbill, I.L. Chernyavsky, B. Bottalico, G. Desoye, S. Hansson, G. Kenna, L.E. Knudsen, U.R. Markert, N. Powles-Glover, H. Schneider, L. Leach, An international network (PlaNet) to evaluate a human placental testing platform for chemicals safety testing in pregnancy, Reprod Toxicol 64 (2016) 191-202.

2. O.E. Jensen, I.L. Chernyavsky, Blood flow and transport in the human placenta. Annu Rev Fluid Mech 51 (2019) 25-47. doi:10.1146/annurev-fluid-010518-040219.

3. M. Rothbauer, N. Patel, H. Gondola, M. Siwetz, B. Huppertz, P. Ertl, A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines. Sci Rep 7(1) (2017) 5892. 4.

4. Okae H, Toh H, Sato T, et al. Derivation of Human Trophoblast Stem Cells. Cell Stem Cell. 22(1) (2018) 50‐63.e6. doi:10.1016/j.stem.2017.11.004


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