FREE PhD Study Fairs in Sheffield & Edinburgh | REGISTER NOW FREE PhD Study Fairs in Sheffield & Edinburgh | REGISTER NOW

Utilising small molecule NLRP3 inflammasome inhibitors to treat placental inflammation observed in chronic histiocytic intervillositis, fetal growth restriction and stillbirth


   Faculty of Biology, Medicine and Health

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr A Heazell, Dr P Brownbill, Dr A Stevens, Prof John Aplin  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Delayed villous maturation (DVM) describes a condition in the placenta that is usually seen after 36 weeks and rarely before 34 weeks of pregnancy. DVM is characterized by a monotonous villous population with reduced numbers of syncytio-vascular membranes for the period of gestation, as well as a continuous cytotrophoblast layer and centrally placed capillaries [1]. DVM is strongly associated with stillbirth [2, 3] and is thought to be associated with maternal diabetes and reduced oxygenation in the fetus [4-6]. However, DVM is also associated with other seemingly unrelated risk factors such as use of opiates and fetal abnormalities [7]. There is a need to make DVM a reproducible diagnosis, in order that it can be better explored and understood [8].

This PhD programme would investigate three main aims

i) To provide a reproducible measure of DVM which can be applied to a series of clinical placental samples to investigate the transcriptome;

ii) To investigate which clinical characteristics are associated with clinically significant DVM determined by this reproducible measure;

iii) To use a vascular culture model to determine whether factors implicated in DVM such as hyperglycaemia affect placental vascular development.

To achieve the first aim we will collect placental tissue from 36 weeks of pregnancy through to 41 weeks of pregnancy. We will then use semi-automated analysis of placental structure to determine numerical limits for normal placental structure at these stages of pregnancy. This will help give a clear definition of DVM.

We will then obtain placental samples from stillbirths classified as DVM and those with no placental abnormality. We plan to compare these samples using spatial transcriptomic approaches. This will enable us to determine whether DVM has a specific signature and if so, whether this affects relevant signalling pathways. We will use a modelling to see whether there is a relationship between RNAseq data and structure.

We will use established models of endothelial cell culture (Human Placental Arterial Endothelial Cells) to determine the effects of environments implicated in DVM (e.g. high blood sugar seen in diabetes). We will look at whether the RNA signature is similar to that seen in the ex vivo DVM samples.

Ultimately, these experiments will enable us to better understand what an observation of DVM means, and how we could alter management in a future pregnancy e.g. closer examination of blood sugar, gestational weight gain.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with experience in reproductive medicine or pharmacy are encouraged to apply

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.

Equality, Diversity and Inclusion

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

Funding source - Tommy’s
PhD stipend £16,000 per annum, Fees - £4,700 per annum, Consumables £5,000 per annum

References

1. Khong, T.Y., et al., Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch Pathol Lab Med, 2016. 140(7): p. 698-713.
2. Ananthan, A., et al., Placental Findings in Singleton Stillbirths: A Case-control Study. J Trop Pediatr, 2019. 65(1): p. 21-28.
3. Ruschkowski, B., et al., Gastroschisis Is Associated With Placental Delayed Villous Maturation. Pediatr Dev Pathol, 2020. 23(3): p. 197-203.
4. Higgins, M., F.M. McAuliffe, and E.E. Mooney, Clinical associations with a placental diagnosis of delayed villous maturation: a retrospective study. Pediatr Dev Pathol, 2011. 14(4): p. 273-9.
5. Jaiman, S., et al., Disorders of placental villous maturation in fetal death. J Perinat Med, 2020.
6. Jaiman, S., et al., Placental delayed villous maturation is associated with evidence of chronic fetal hypoxia. J Perinat Med, 2020. 48(5): p. 516-518.
7. Serra, A.E., et al., Delayed villous maturation in term placentas exposed to opioid maintenance therapy: a retrospective cohort study. Am J Obstet Gynecol, 2017. 216(4): p. 418 e1-418 e5.
8. Treacy, A., et al., Delayed villous maturation of the placenta: quantitative assessment in different cohorts. Pediatr Dev Pathol, 2013. 16(2): p. 63-6.
PhD saved successfully
View saved PhDs