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  Complement-inflammasome interactions in amyloid-beta-induced inflammation


   Cardiff School of Medicine

   Friday, August 30, 2024  Self-Funded PhD Students Only

About the Project

This is a Self-Funded/Sponsored PhD opportunity.

FUNDING REQUIRED:

  • Full UK/EU or International Tuition Fees
  • UK Living Expenses
  • Bench Fees (£45,000 total)

Open to all students of any nationality without restrictions (UK/EU and International)

Alzheimer’s disease (AD) is a neurodegenenerative disease characterised by progressive loss of memory and cognitive dysfunction. AD is defined by the deposition of amyloid-β (Aβ) in the brain, the formation of neurofibrillary tangles and persistent neuroinflammation. Neuroinflammation is triggered in response to the deposition and aggregation of Aβ in the brain tissue and is believed to drive ongoing pathology. Several families of innate immune receptors or sensors have been linked with Aβ recognition and neuroinflammation in AD.

While it is known that Aβ can serve as a trigger of neuroinflammation there is a gap in our understanding of the cellular mechanisms underlying this process.

Pattern recognition receptors (PRRs) such as Toll-like and Nod-like receptors (TLRs, NLRs respectively), together with the complement system have been individually linked to AD, but there is now increasing evidence for extensive bidirectional cooperation between these different parts of the innate immune system which shapes the immune response through synergistic crosstalk. TLR expression is upregulated in the AD brain, and in murine models of AD, TLR2 and TLR7 were found to be upregulated compared to controls, whereas the NLRP3 inflammasome, a central inflammatory signalling hub has been linked to the recognition of Aβ and the release of IL-1β. In the case of the complement system, both the classical and alternative complement pathways are directly activated by Aβ in an antibody-independent fashion. In particular, the classical pathway has been shown to be directly activated in AD by both fibrillar Aβ deposits and neurofibrillary tangles. All components of the classical pathway and the alternative pathway have been identified on neuronal cells in the AD brain. The end product of the terminal pathway, the cytotoxic and inflammatory membrane attack complex (MAC), was also found on neuronal membranes and in amyloid plaques of the AD brain.

Both complement and the NLRP3 inflammasome have been separately linked to AD. It is our hypothesis that the key to the chronic inflammatory response to Aβ is the synergistic complement-inflammasome interaction resulting in an augmented inflammatory response that damages the CNS. A combinational therapy targeting both pathways might be the best approach to alleviate the symptoms of the disease. Using RNASeq, immunohistochemistry, confocal microscopy, CRISPR knockouts and cytokine assays we will test our hypothesis, by answering the following questions:

•       Is there interplay between the complement and inflammasome pathways in AD?

•       What is the role of Aβ in the activation of the complement system & the inflammasome?

•       Which signalling events link complement and inflammasome activation in response to Aβ?

•       Could inhibition of the signalling triggered lead to inhibition of inflammasome activation and IL-1β/IL-18 secretion?

Entry Requirements  

You will hold or expect to achieve a First or Upper Second Class degree in a relevant subject. As this is a training doctorate, previous research experience is not essential.

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS). 

How to Apply  

This studentship has a start date of October 2024. In order to be considered you must submit a formal application via Cardiff University’s online application service.

There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2024). This will take you to the application portal. 

In order to be considered candidates must submit the following information: 

 • Supporting statement 

• CV 

• Qualification certificates 

• References x 2 

• Proof of English language (if applicable) 

Medicine (26)

Funding Notes

This is a 3 year Self-Funded/Sponsored PhD opportunity.
FUNDING REQUIRED:
Full UK/EU or International Tuition Fees
UK Living Expenses
Bench Fees (£45,000 total)
Open to all students of any nationality without restrictions (UK/EU and International)

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