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  The role of the NLRP3 inflammasome in chemotherapy-induced neurotoxicity


   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)

Patients suffering from cancer receiving cytotoxic chemotherapeutic agents such as platins and taxanes (paclitaxel and oxaliplatin) develop neurological toxicities, such as peripheral neuropathy and ototoxicity, which can severely impact their day-to-day functioning – collectively called chemotherapy-induced peripheral neuropathy (CIPN). CIPN affects up to 90% of cancer patients. The sensory symptoms of CIPN include numbness, loss of proprioception, tingling, spontaneous burning, shooting or electric shock like pain, and cold hypersensitivity among others. Affected patients struggle with daily activities, have a low quality of life, and might stop cancer treatment. Unfortunately, there are no effective prophylactic or therapeutic treatments for these side effects. Many studies point to the involvement of inflammasome as a major contributor of CIPN pathology. On this study, we will investigate the role of the NLRP3 inflammasome in chemotherapy-induced inflammation.

Project aims:

The current proposal aims to unravel the molecular mechanisms of innate immune activation in neurons in response to chemotherapy treatment 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 transcriptomic (RNASeq) datasets in order to determine innate immune pathways activated in response to chemotherapy agents.
  • Determine the role the NLRP3 inflammasome in chemotherapy induced inflammation by knocking out the NLRP3 inflammasome in neurons and determining inflammatory responses
  • Modulate chemotherapy-induced inflammation in neurons, by inhibiting the NLRP3 pathway- using compounds

 During the first year, the student will focus on RNASeq on neurons stimulated with chemotherapy drugs in order to identify the innate immune pathways involved. Once pathways have been identified, the student will use CRISPR in order to knock out one of the pathways of interest in neuronal cell lines and subsequently challenge the cells with chemotherapy drugs to determine inflammasome activation. In Year 2 & 3, the student will continue validating identified pathways using CRISPR as well as determine the metabolic pathways involved. Immunohistochemistry and confocal microscopy will also be used. Compounds that inhibit the NLRP3 will be used in order to validate the NLRP3 involvement in CIPN.

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)

Register your interest for this project



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