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Exploration of neurological tumour derivation across the blood brain barrier and development of anti-metastatic therapy

   Cardiff School of Medicine

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  Dr T Martin, Prof Wen Jiang, Prof Ping Dou  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Summary of project: This project seeks to explore the mechanisms whereby the blood brain barrier can be breached during metastatic progression and the development of a drug/s that can modulate the response of brain endothelial cells during this process. Currently this is still poorly understood and given the complexity of tight junction composition controlling blood brain barrier permeability this is unsurprising. We have several potential drugs that the student can develop further that have the ability to modulate the blood brain barrier. The study will evaluate the research question – Can modification of chemotherapeutics can improve efficacy across the BBB in patients with metastatic cancer and can provide an insight into the mechanisms underpinning tumour-originated changes in brain endothelial Tight Junctions?

We have considerable expertise in the area of tight junction and blood brain barrier research and have previously collaborated with an industrial partner in the development of a drug that is successfully able to penetrate the blood brain barrier and treat HER2+ breast cancer metastatic disease. The student would contribute to tailoring the project with a decision on the type of cancer model used (breast, lung, prostate) and later by evaluating the best candidate compounds.

 Project plan:

Phase 1 - After a consultation and preparation period, the student will have become familiar with the background of the project and the clinical and scientific questions that need to be answered. This will give them the opportunity and knowledge to contribute to the pathway of the project and make informed decisions. The initial plan would be to generate modified compounds permeable to/able to alter permeability of the BBB. Base compounds will be modelled in silico and new variants manufactured. The compounds derived will be then tested using our BBB in vitro model. We have available three human endothelial cells lines and associated astrocytes etc for 3D modelling and assessing changes in endothelial cell permeability and behaviour. There will be assessment of effects of cell behaviour using our available equipment and facilities (TEER, electric cell impedance sensing (ECIS), live cell imaging).

Phase2 – Student-led assessment and decision on the compounds to take forward for in vitro analysis to assess the mechanisms underpinning changes in the BBB. Such methods to include quantitative PCR analysis, protein microarrays, fluorescent imaging of co-culture models, protein expression to assess changes in phosphorylation status of TJ proteins and increases/decreases in expression, immunofluorescence to assess changes in protein location and intensity, cell shape. 

Phase 3 – In vivo murine model using whole body imaging and tracking (18F-FDG (10MBq) and PET/CT scanning) to assess BBB permeability, effects on tumour metastatic spread and passage across the BBB, effectiveness in enabling chemotherapeutics to also penetrate the BBB and provide evidence of efficacy against secondary tumours. Evaluation of which compound will be taken forward for IP.

Key words: Blood brain barrier, Metastasis, Tight junctions, Drug development

Application Process

We are seeking enthusiastic and motivated students with an interest in Cancer or genomic research. Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject.

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

Following discussion with proposed supervisors and to be considered you must submit a formal application via Cardiff University’s online application service. Medicine - Study - Cardiff University

The total duration of this PhD programme is 3 years. 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’ (i.e. April 2022). This will take you to the application portal.

In the ‘Research Proposal’ section of the application enter the name of the project you are applying to.

Candidates must submit the following information:

  • Supporting statement 
  • CV 
  • Qualification certificates 
  • Proof of Funding i.e. a letter of intent from your sponsor or confirmation of self-funded status.
  • References x 2 
  • Proof of English language (if applicable)

Closing date for applicants is the 28th February 2022.

Funding Notes

This is a Self-Funded/Sponsored PhD opportunity.
Full UK/EU or International Tuition Fees
UK Living Expenses
Bench Fees (where applicable)
Open to all students of any nationality without restrictions (UK/EU and International)
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