(MRC DTP) Investigating the protective properties of angiotensin-converting enzyme inhibitors after haemorrhagic stroke
About the Project
Intracerebral haemorrhage (ICH) is a catastrophic form of stroke caused by spontaneous bleeding in the brain and is a leading global cause of adult disability. There is an urgent requirement to identify widely accessible and effective acute medical treatments to reduce brain injury caused by ICH (Withers et al, 2020). Angiotensin converting enzyme inhibitors (ACE-I) are a widely used class of renin-angiotensin aldosterone system inhibitors that act as blood pressure lowering medications to prevent and/or treat cardiovascular diseases, including stroke. Although primarily used to manage hypertension, increasing evidence indicates that ACE-I may offer cellular protection via an antioxidant function (Wzgarda et al, 2017). Using an unbiased zebrafish drug screening approach, we have shown that the ACE-Is, ramipril and quinapril, significantly reduce brain cell death acutely after spontaneous brain haemorrhage (Crilly et al, 2018; Crilly et al, 2022). Furthermore, our recent unpublished work shows that acute ACE-I treatment is associated with a significant reduction in brain cell death in a mouse model of ICH. We have also shown that ACE-Is may be promising clinically. We found treatment with an ACE-I after ICH to be independently associated with better 90-day recovery in 2611 participants in the INTERACT2 clinical trial (Anderson et al, 2013; Crilly et al, 2022). Preliminary data obtained from the zebrafish ICH model indicates that acute ACE-I treatment is associated with reduced mitochondrial protein expression and decreased mitochondrial stress. Given mitochondrial dysfunction is a significant contributor to brain injury, we hypothesise that ACE-I treatment offers neuroprotection after ICH by reducing mitochondrial stress. To study this hypothesis, we will utilise a combination of zebrafish and in vitro models of ICH with live imaging, flow cytometry, transcriptomics and molecular biology to determine the mechanisms associated with ACE-I treatment and neuroprotection after ICH. This study will provide translational insight to support a role for ACE-Is in post-ICH treatment and will provide essential mechanistic information for future clinical studies.
https://www.braininflamelab.org/
https://research.manchester.ac.uk/en/persons/paul.kasher
https://research.manchester.ac.uk/en/persons/adrian.parry-jones
https://research.manchester.ac.uk/en/persons/stuart.allan
Eligibility
Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – on the application form you must select MRC DTP PhD Programme. If you select the incorrect programme your application cannot be considered. Full details on how to apply can be found on the MRC DTP website
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our FBMH.doctoralacademy.admissions@manchester.ac.uk
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
Funding Notes
Studentship funding is for 4 years and covers tuition fees and an annual stipend. This does not include any costs associated with relocation.
References
Crilly S, Njegic A, Laurie SE, Fotiou E, Hudson G, Barrington J, Webb K, Young HL, Badrock AP, Hurlstone A, Rivers-Auty J, Parry-Jones AR, Allan SM, Kasher PR. Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage. F1000Res. 2018 Oct 8;7:1617. doi: 10.12688/f1000research.16473.2.
Crilly S, Parry-Jones A, Wang X, Selley JN, Cook J, Tapia VS, Anderson CS, Allan SM, Kasher PR. Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage. Dis Model Mech. 2022 Mar 1;15(3):dmm049227. doi: 10.1242/dmm.049227.
Withers SE, Parry-Jones AR, Allan SM, Kasher PR. A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research. Transl Stroke Res. 2020 Dec;11(6):1229-1242. doi: 10.1007/s12975-020-00830-z.
Wzgarda A, Kleszcz R, Prokop M, Regulska K, Regulski M, Paluszczak J, Stanisz BJ. Unknown face of known drugs - what else can we expect from angiotensin converting enzyme inhibitors? Eur J Pharmacol. 2017 Feb 15;797:9-19. doi: 10.1016/j.ejphar.2016.12.031.
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