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  The role of the NLRP3 inflammasome in kidney disease


   Cardiff School of Medicine

   Friday, May 31, 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)

The prevalence of both acute kidney injury (AKI) and chronic kidney disease (CKD) is rising worldwide and is associated with significant multimorbidity and mortality. AKI accounts for up to 10-15% of hospital admission (Wonnacott et al., 2014). If left untreated, it can progress CKD); prevalent in 13% of world populations) (Romagnani et al., 2017) and the patients may end up requiring renal replacement therapy, which can be in the form of dialysis of transplant.

Ischaemia reperfusion injury (IRI) is the main underlying mechanism in AKI and is inevitable in kidney transplantation (Ponticelli, 2014). AKI can result in delayed graft function and can affect the outcome of the transplantation (Mannon, 2018). Therefore, identifying mechanisms which can minimise the deleterious effects of the IRI and critical to promoting the longevity of kidney transplants.

The innate immune system and, the NLRP3 inflammasome has been linked with kidney disease, but the molecular mechanisms involved have yet to be deciphered. The current proposal aims at unravelling the molecular mechanisms involved in NLRP3-driven kidney disease.

Project Research Aim

The current proposal aims to unravel the molecular mechanisms of innate immune activation in kidney disease using a combination of bioinformatics, molecular biology, biochemistry as well as non-invasive imaging techniques (to determine molecular interactions and signal transduction). By combining these techniques, we will:

  • Perform bioinformatics analysis of publicly available single cell RNA seq (scRNA-seq) datasets.
  • Determine the role the NLRP3-induced inflammation in kidney fibroblasts by knocking out the NLRP3 inflammasome and determining inflammatory responses.
  • Modulate inflammation in kidney fibroblasts, by inhibiting the NLRP3 pathway- using compounds.

We will use publicly available murine scRNA-seq datasets (1) to compare innate immune signatures characterising adaptive and fibrotic repair for different cell types. The data is readily available for download and also as an interactive website. Our focus will be on comparing gene expression at day 14 with baseline for long and short IRI. Once innate immune pathways, such as the NLRP3 inflammasome, have been identified, we will validate their involvement using siRNA or CRISPR in order to knock down the pathway and verify its involvement. In addition, compounds and inhibitors will be used to modulate the innate immune pathways.

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)

References

References:
1. Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration | Nature Communications)

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