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(MRC DTP) Understanding the role of SAMHD1 in haemorrhagic stroke

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  • Full or part time
    Dr P Kasher
    Prof S Allan
    Prof Y Crow
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background: SAM domain and HD domain-containing protein 1 (SAMHD1) is a protein that is known to function as a viral restriction factor and plays a key role in self non-self discrimination (1). Mutation of the SAMHD1 gene causes a genetic subtype of Aicardi-Goutiéres syndrome (AGS) – an inherited inflammatory-based brain disorder associated with enhanced type I interferon (IFN) signalling. Unlike other genetics forms of AGS, SAMHD1-related AGS is associated with a major risk of cerebral vasculopathy and intracerebral haemorrhage (ICH) (2). We have shown that temporal inhibition of the samhd1 gene in zebrafish causes ICH and innate immune phenotypes which are reminiscent of the human condition (Kasher et al., J.Immunol., 2015, doi: 10.4049/jimmunol.1403157). Taken together, these data indicate that SAMHD1 has a currently uncharacterised role in the control of neurovascular integrity. Using CRISPR-Cas9 technology, we have now generated a stable mutant samhd1 zebrafish line. Preliminary whole transcriptomic and phenotypic data indicate that samhd1 mutant larvae exhibit defects in cholesterol biosynthesis pathways and are predisposed to the development of ICH following incubation with sub-threshold doses of atorvastatin – a drug known to inhibit cholesterol production. Interestingly, experimental dysregulation of cholesterol synthesis has been associated with increased activity of IFN signalling (3) and ICH (4).

The aim of this project is to define the mechanistic link between SAMHD1, cholesterol and IFN-related ICH. This project will continue the characterisation of the mutant samhd1 zebrafish phenotype and analyse / verify whole transcriptomic data obtained from different tissue types and stages of life (including a comparison with whole transcriptomic data derived from SAMHD1-related AGS, human, patient material). Further functional investigation will be undertaken using a mutant Samhd1 mouse line (5). Additionally, we will generate brain microvascular endothelial cells using induced pluripotent stem cells derived from SAMHD1-related AGS patient fibroblasts in order to further interrogate the link between dysregulated cholesterol biosynthesis, IFN signalling and ICH. This work will significantly improve our understanding of SAMHD1 function in the context of neurovascular stability and provide translational insight into the role of this molecule in inflammation and ICH.

https://www.research.manchester.ac.uk/portal/paul.kasher.html
https://www.research.manchester.ac.uk/portal/stuart.allan.html
https://www.research.manchester.ac.uk/portal/Yanick.Crow.html
https://www.bmh.manchester.ac.uk/research/domains/neuroscience-mental-health/stroke/

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 www.manchester.ac.uk/mrcdtpstudentships

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.

References

1. Goldstone, D.C., et al., HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature, 2011. 480(7377): p. 379-82.
2. Ramesh, V., et al., Intracerebral large artery disease in Aicardi-Goutieres syndrome implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol, 2010. 52(8): p. 725-32.
3. York, A.G., et al., Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell, 2015. 163(7): p. 1716-29.
4. Eisa-Beygi, S., et al., The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway. Dev Biol, 2013. 373(2): p. 258-66.
5. Rehwinkel, J., et al., SAMHD1-dependent retroviral control and escape in mice. EMBO J, 2013.


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