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Targeting BKCa channels to treat maternal vascular dysfunction in pre-eclampsia


Faculty of Biology, Medicine and Health

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Dr Adam Greenstein , Dr E Cottrell , Dr Stephanie Worton No more applications being accepted Funded PhD Project (Students Worldwide)
Manchester United Kingdom Cardiology Medicine Pharmacology Reproductive Biology Toxicology

About the Project

Globally, pre-eclampsia contributes to 70,000 maternal deaths and 500,000 stillbirths every year. Current treatments are inadequate and babies delivered prematurely due to preeclampsia occupy 1 in 5 neonatal cots in the UK. Improved treatment strategies for pre-eclampsia are urgently needed.

In pre-eclampsia, constriction of maternal small arteries drives hypertension and multiorgan ischaemia. Our previous work suggests large-conductance calcium-activated potassium channels (BKCa) play an important role in relaxing maternal arteries during pregnancy.1 Crucially, the ability of BKCa to relax arteries is preserved in pre-eclampsia, suggesting BKCa may offer a new strategy for treating vascular dysfunction in pre-eclampsia and improving pregnancy outcomes.1

Outside of pregnancy, several BKCa activators have been investigated for their potential clinical antihypertensive effects. Human beta-defensin 2 (HBD-2), an endogenous antimicrobial peptide produced in the epithelium, and Neolignan-1, a plant-derived phenol, are naturally-occurring BKCa activators which cause relaxation in isolated arteries and decrease blood pressure in primate or rat models,2,3 yet neither have been investigated in pregnancy.

This 3-year PhD project will investigate the use of BKCa activators (such as HBD-2 and Neolignan-1) as potential new treatments for maternal vascular features of pre-eclampsia. Experimental work will assess the expression of BKCa channel subtypes (IHC/PCR) and the functional effects of BKCa activators in intact arteries obtained from women with normal pregnancy and those with pre-eclampsia. Subsequently, the ability of HBD-2 and/or Neolignan-1 to reduce blood pressure and improve pregnancy outcomes in an animal model of hypertensive pregnancy will be determined.

This project will provide pre-clinical evidence regarding the suitability of treating vascular dysfunction in pre-eclampsia with BKCa activators. Positive findings from this study would lead to further investigations of the safety of BKCa activators in pregnancy prior to conducting a human clinical trial of their use. 

https://www.braininflamelab.org

Entry Requirements:

Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in a biology-related discipline. A Master’s degree in a relevant subject and experience in Cardiovascular or Reproductive Sciences are desirable. 

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. You MUST also submit an online application form - choose PhD Cardiovascular Sciences.

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 project is funded by Tommy's. Studentship funding is for a duration of three years to commence in September 2021 and covers UK tuition fees and a stipend (approximately £15,000 per annum 21/22) 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 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 scheme.

References

1. Worton SA, Pritchard HAT, Greenwood SL, Alakwari M, Heazell AEP, Wareing M, Greenstein A, Myers JE. Kynurenine relaxes arteries of normotensive women and those with preeclampsia. Circ Research. 2021. Accepted 18th January 2021.
2. Liu R, Zhang Z, Liu H, et al. Human β-Defensin 2 Is a Novel Opener of Ca 2+ -Activated Potassium Channels and Induces Vasodilation and Hypotension in Monkeys. Hypertension.2013;62:415–425. http://www.ncbi.nlm.nih.gov/pubmed/23734009.
3. Singh A, Kumar BS, Iqbal H, et al. Antihypertensive activity of diethyl-4,4ʹ-dihydroxy-8,3ʹ-neolign-7,7ʹ-dien-9,9ʹ-dionate: A continuation study in L-NAME treated wistar rats. Eur J Pharmacol. 2019;858:172482.https://www.sciencedirect.com/science/article/pii/S0014299919304340?via%3Dihub.
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