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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

  , ,  Saturday, October 15, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

There is increasing evidence that sterile placental inflammation is an underlying cause of placental dysfunction, and contributes to the pathology of chronic histiocytic intervillositis (CHI), villitis of unknown etiology (VUE), fetal growth restriction (FGR) and stillbirth [1-3]. There are currently no effective treatments for placental inflammation and little work has been done to screen suitable drug candidates, current treatments are based on empirical studies. We have recently identified a role for the NLRP3 inflammasome in mediating placental inflammation [1, 4], and have established a robust ex vivo model in which to study inflammation in placental explants [4]. We now have access to a range of small molecule NLRP3 inhibitors, which have been shown to significantly reduce inflammation in both human and mouse cells [5, 6]. The aim of this project is assess whether these NLRP3 inhibitors represent a safe and efficacious treatment for placental inflammation.

Our objectives are to:

·      Screen a panel of NLRP3 inhibitors to identify candidates which reduce one or more markers of placental inflammation in our ex vivo explant model.

·      Assess whether reduced placental inflammation is accompanied by an improvement in one or more aspects of placental function.

·      Evaluate whether the efficacy of the NLRP3 inhibitors is maintained, when encapsulated into targeted liposomes.

·      Examine whether systemic or targeted delivery of NLRP3 inhibitors can improve pregnancy outcome in a mouse model of placental inflammation (e.g. Advanced Maternal Age, Moderately Aged Mouse, eNOS knockout mouse).

This work will inform the development of novel therapeutics to treat the placental inflammation observed in chronic histiocytic intervillositis, VUE, fetal growth restriction and stillbirth.

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.

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

How To Apply

To be considered for this Studentship you MUST submit a formal online application form - full details on how to apply can be found on https://www.bmh.manchester.ac.uk/study/research/apply/

Please select PhD Reproductive Sciences under academic programme when completing your online application. 

Please do not submit an application until you have discussed your suitability to the project with the Primary Supervisor

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

This studentship is funded by Tommy’s and is for a duration of 3.5 years to commence in January 2023 and covers fees, a stipend (£16,000 per annum 23/24) and consumables.
Funding will cover UK tuition fees and stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a scholarship that will enable a full studentship to be awarded to international applicants. This full studentship will only be awarded to exceptional quality candidates, due to the competitive nature of this funding.

References

[1] Girard et al. Circulating cytokines and alarmins associated with placental inflammation in high-risk pregnancies. Am. J. Reprod. Immunol. 2014;72:422–434.
[2] Derricott et al. Characterizing Villitis of Unknown Etiology and Inflammation in Stillbirth. Am. J. Pathol. 2016;186:952–961.
[3] Sharps et al. Increased placental macrophages and a pro-inflammatory profile in placentas and maternal serum in infants with a decreased growth rate in the third trimester of pregnancy. Am. J. Reprod. Immunol. 2020;84:e13267.
[4] Baker et al. Hypoxia and oxidative stress induce sterile placental inflammation in vitro. Sci Rep. 2021;11(1):7281.
[5] Redondo-Castro at al. Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses. Sci Rep. 2018;8(1):5667.
[6] Baldwin et al. Design, Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome. ChemMedChem. 2018;13(4):312-320.

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