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(MRC DTP) Investigating the role of neuroinflammation and cholesterol metabolism in the progression of brain injury following intracerebral haemorrhage


Project Description

Intracerebral haemorrhage (ICH) is a type of stroke caused by spontaneous bleeding within the brain. The toxic influx of blood into the brain initiates an immune response that induces activation of microglia, infiltration of peripheral leukocytes and the production of inflammatory cytokines, including interleukin-1β (IL-1β). Such processes are thought to drive the progression and potential recovery of brain injury following ICH, and represent a realistic therapeutic target.

An increasing body of evidence exists to support a role for cross-talk between cholesterol metabolism and the immune system. Cholesterol 25-hydroxylase (CH25H) is an enzyme that can be upregulated following inflammatory stimulation that catalyses the conversion of cholesterol into 25-hydroxycholesterol (25-HC). Subsequently, 25-HC can inhibit inflammation, and IL-1β has been shown to be one of its targets1. Given the known pro-inflammatory function of IL-1β in the pathogenesis of brain injury, the aim of this study is to further define its relationship with CH25H in the context of ICH.

We have recently described the use of zebrafish larvae for studying brain injury and neuroinflammation following ICH2,3. Preliminary transcriptomic data indicate that during the acute injury phase, ch25h gene expression is significantly impaired at a time when il-1β expression is significantly upregulated. Furthermore, immunohistochemical assessment of chronic patient ICH post-mortem brain sections has shown that IL-1β protein expression is reduced which correlates with a strong CH25H signal within the perihaematomal region. These data suggest that an inverse relationship may exist between CH25H and IL-1β in the brain injury response following ICH.

This project will further characterise CH25H and IL-1β protein expression patterning using immunohistochemistry in a cohort of post-mortem human ICH samples. We will generate transgenic zebrafish fluorescent reporter lines for both ch25h and il-1β and characterise the spatiotemporal expression patterning of both genes during the injury/recovery phases following ICH using live imaging. In addition, we will generate a conditional transgenic line that overexpresses ch25h specifically within leukocytes following chemical induction, to determine the effects on brain injury and il-1β signalling following ICH in zebrafish. We will also induce ICH in a mutant Ch25h mouse model to determine effects on disease outcomes. Furthermore, we will utilise an in-vitro approach to determine the effects of CH25H/25HC dysregulation on inflammasome formation and activation in primary mouse bone marrow derived macrophages4. This work will provide critical new insight into how cholesterol metabolism may regulate inflammation during the injury phase in haemorrhagic stroke.

https://www.research.manchester.ac.uk/portal/paul.kasher.html

https://www.research.manchester.ac.uk/portal/david.brough.html

https://www.research.manchester.ac.uk/portal/stuart.allan.html

https://www.research.manchester.ac.uk/portal/adrian.parry-jones.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Reboldi, A. et al. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345, 679-84 (2014).
2. Crilly, S. et al. Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage. F1000Res 7, 1617 (2018).
3. Crilly, S., Njegic, A., Parry-Jones, A.R., Allan, S.M. & Kasher, P.R. Using Zebrafish Larvae to Study the Pathological Consequences of Hemorrhagic Stroke. J Vis Exp (2019).
4. Green, J.P. et al. Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. Proc Natl Acad Sci U S A 115, E9371-E9380 (2018).

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