Hypoxia and HIF signalling in TME as regulators of pro- and anti- tumour-associated immune cell functions (ref: SF22/HLS/APP/GIELING)


   Faculty of Health and Life Sciences

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  Dr R Gieling  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Hypoxia (low oxygen tension) and hypoxia-inducible factor (HIF)-1 and HIF-2 signalling are environmental cues on the immune system in both acute and chronic human diseases. Within the tumour microenvironment (TME), various studies have revealed the complex relationship between hypoxia/HIF signalling and immune cells of the innate and adaptive immunity. Hypoxia and HIF signalling modulate the pro-and anti-tumour functions in immune cells (e.g. switch between M1 and M2 phenotype macrophages and level of NK anti-tumour activity). Hypoxia also stimulates the differentiation of human CD8+ T cells into tissue-resident memory T cell (TRM) in TME, increasing the antitumour immunity. Hypoxic tumour cells actively contribute to the immune response in TME e.g. by release of exosomes enriched with chemokines and chemoattractants. Hypoxic tumour cells are also able to modulate the TME immunity using HIF-1α/β target genes like carbonic anhydrase IX (CAIX) and monocarboxylate transporter 4 (MCT4), both involved in TME acidosis. We have previously shown the importance of hypoxia and HIF/CAIX signalling on cancer progression (tumour growth, metastases formation and therapy response) (see Ref 1-4).

In this project, you will be exploring the role of pH regulatory enzymes, CAIX and MCT4, associated with hypoxic/HIF signalling cancer cells and their role in TME immunity to unravel some of its complexity. You will be using therapeutic interventions which will include specific monoclonal antibodies, low molecular weight inhibitors and liposome-based formulations in cell cultures of human cancer cells. You will be using various cell culture techniques including working with spheroids from cancer cells and mixed-cell spheroids, advanced cell viability/migration/invasion assays, biochemistry (western blotting, Elisa), immunocytochemistry (including the use of fluorescent cell tracers and pH-sensitive fluorescent indicators). Additionally, RNA interference technologies (like siRNA) will be used to silence the CA9 and/or MCT4 gene expression in human cancer cells. We will establish FACS methods for identification and characterization of different immune cell types in cancer patient peripheral blood and tumour samples.

Eligibility and How to Apply:

Please note eligibility requirement:

•      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non- UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above)

•      Appropriate IELTS score, if required

For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

 

Please note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. SF22/…) will not be considered.

 

Deadline for applications: Ongoing

Start Date: 1st October and 1st March are the standard cohort start dates each year.

Northumbria University is committed to creating an inclusive culture where we take pride in, and value, the diversity of our doctoral students. We encourage and welcome applications from all members of the community. The University hold a bronze Athena Swan award in recognition of our commitment to advancing gender equality, we are a Disability Confident Employer, a member of the Race Equality Charter and are participating in the Stonewall Diversity Champion Programme. We also hold the HR Excellence in Research award for implementing the concordat supporting the career development of researchers.

Informal enquiries to Dr Roben Gieling ([Email Address Removed])

Biological Sciences (4)

Funding Notes

This project is fully self-funded and available to applicants worldwide. Tuition fees will depend on the running cost of the individual project, in line with University fee bands found at https://www.northumbria.ac.uk/study-at-northumbria/fees-funding/. The fee will be discussed and agreed at interview stage.
Please note: to be classed as a Home student, candidates must meet the following criteria:
Be a UK National (meeting residency requirements), or
have settled status, or
have pre-settled status (meeting residency requirements), or
have indefinite leave to remain or enter.
If a candidate does not meet the criteria above, they would be classed as an International student.

References

Alghamdi, Amira. Development of Nanoscale Drug Delivery System for Treatment of Cancers Expressing GRPR and CAIX Targets (2021). Web.
Bryant JL, Gieling RG, Meredith SL, Allen TJ, Walker L, Telfer BA, Supuran CT, Williams KJ, White A. Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer. Int J Cancer. 2018 Jan 1;142(1):191-201. doi: 10.1002/ijc.31042. Epub 2017 Oct 3. PMID: 28905987.
Gieling RG, Fitzmaurice RJ, Telfer BA, Babur M, Williams KJ. Dissemination via the lymphatic or angiogenic route impacts the pathology, microenvironment and hypoxia-related drug response of lung metastases. Clin Exp Metastasis. 2015 Aug;32(6):567-77. doi: 10.1007/s10585-015-9728-z. Epub 2015 Jun 26. PMID: 26112891.
Gieling RG, Parker CA, De Costa LA, Robertson N, Harris AL, Stratford IJ, Williams KJ. Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro. J Enzyme Inhib Med Chem. 2013 Apr;28(2):360-9. doi: 10.3109/14756366.2012.736979. Epub 2012 Nov 19. PMID: 23163664.

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