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Dr G Mavria,
Dr S Bell,
Dr C Toomes
Applications accepted all year round
Self-Funded PhD Students Only
Leeds
United Kingdom
Biochemistry
Bioinformatics
Cancer Biology
Cell Biology
Genetic Engineering
Immunology
Molecular Biology
Neuroscience
About the Project
Glioblastoma is a deadly brain tumour treated with surgery, radiotherapy and chemotherapy with patient survival of 6-15 months. Our previous work investigated changes in the microenvironment of glioblastoma tumours that have become resistant to radiotherapy, using patient samples and an in vivo model of glioblastoma recurrence following radiotherapy. We found vascular changes in recurrent tumours that elevate hypoxia, thus promoting invasiveness to the normal brain and resistance to further treatment. RNA sequencing revealed upregulation of ligands that activate Wnt signaling, associated with altered blood vessel morphology and function. During normal development Wnt ligands bind Frizzled and other receptors to control gene transcription, proliferation and differentiation. Deregulation of Wnt signaling in cancer cells, or the tumour microenvironment (immune cells, fibroblasts, blood vessels) is associated with malignancy. Our aim is to understand the role of Wnt ligands in glioblastoma recurrence using knockdown and overexpression approaches employing 3-dimensional culture and in vivo recurrence models established in our lab. Furthermore, we will analyze differential ligand expression in patient samples of primary and recurrent glioblastoma tumours (paired). We will assess the efficacy of Wnt inhibitors in combination with radiotherapy, aiming to improve response to radiotherapy and survival of patients with recurrent glioblastoma.
Techniques associated with this project:
The student will gain experience in a wide range of techniques and approaches including CRISPR, western blotting, RNA sequencing, culture model of perfused endothelial tubes in microfluidic devices, in vivo model of radiotherapy treatment, confocal imaging, immunohistochemical and immunofluorescence analysis of patient samples, Image J software analysis.
This project is part of the International PhD Academy: Medical Research
Eligibility:
You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.
Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements are:
- British Council IELTS - score of 7.0 overall, with no element less than 6.5
- TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.
How to apply:
Applications can be made at any time. To apply for this project applicants should complete an online application form and attach the following documentation to support their application.
- a full academic CV
- degree certificate and transcripts of marks
- Evidence that you meet the University's minimum English language requirements (if applicable)
To help us identify that you are applying for this project please ensure you provide the following information on your application form;
- Select PhD in Medicine, Health and Human Disease as your programme of study
- Give the full project title and name the supervisors listed in this advert
Any queries regarding the application process should be directed to fmhpgradmissions@leeds.ac.uk
Funding Notes
This project is aimed at International applicants who are able to self fund their studies or who have a sponsor who will provide their funding.
References
1) Radiotherapy promotes hypoxia and peritumoural angiogenesis in glioblastoma recurrences through a switch in angiogenic factor expression. Egnuni T, Widyadari A, Shakeel A, Grant M, Heskin L, Shires M, Shaw G, Taylor A, Chakrabarty A, Speirs V, Lorger M, Short SC, Wurdak H, Mavria G. (in preparation).
2) GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models (2021). Brüning-Richardson A, Shaw GC, Tams D, Brend T, Sanganee H, Barry ST, Hamm G, Goodwin RJA, Swales JG, King H, Steele L, Morton R, Widyadari A, Ward TA, Esteves F, Boissinot M, Mavria G, Droop A, Lawler SE, Short SC. Cancers 13:5939.
3) Abraham S, Scarcia M, Bagshaw RD, McMahon K, Grant G, Harvey T, Yeo M, Esteves FO,
Thygesen HH, Jones PF, Speirs V, Hanby AM, Selby PJ, Lorger M, Dear TN, Pawson T, Marshall CJ
and Mavria G (2015). A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis Nat Commun. 6, 7286.
2) GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models (2021). Brüning-Richardson A, Shaw GC, Tams D, Brend T, Sanganee H, Barry ST, Hamm G, Goodwin RJA, Swales JG, King H, Steele L, Morton R, Widyadari A, Ward TA, Esteves F, Boissinot M, Mavria G, Droop A, Lawler SE, Short SC. Cancers 13:5939.
3) Abraham S, Scarcia M, Bagshaw RD, McMahon K, Grant G, Harvey T, Yeo M, Esteves FO,
Thygesen HH, Jones PF, Speirs V, Hanby AM, Selby PJ, Lorger M, Dear TN, Pawson T, Marshall CJ
and Mavria G (2015). A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis Nat Commun. 6, 7286.
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