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Exploring the function of the cGAS-STING pathway in oral tissues: links to ageing, response to infection and oncogenesis


Project Description

Background: The ability of cells to detect cytoplasmic DNA is an important part of the innate immune response. DNA can be present in the cytoplasm of cells if infected (viral or bacterial) and the cGAS-STING pathway is a key mechanism for the detection of and response to this DNA. Activation of cGAS-STING results in stimulation of inflammatory mediator release, including interferons and other cytokines. In addition to infection, there are other potential sources of cytoplasmic DNA: as cells age, they can undergo senescence and this process may lead to the release of DNA from the nucleus of the cell into the cytoplasm. Similarly, in cancer development, genomic instability can result in accumulation of cytoplasmic DNA. Thus, the cGAS-STING pathway lies at the intersection of a number of pathogenic mechanisms in oral disease. Understanding the role of cGAS-STING in oral disease opens up potential for new treatment approaches for infectious disease, age related pathology and cancer. Objectives: To assess the functions of the cGAS-STING pathway in oral epithelial cells and oral fibroblasts in response to a number of stimuli including bacterial infection, senescence and in cancer cells with a range of genomic instability, including those with and without viral (HPV) infection. Novelty and timeliness: other than one report of alterations in the cGAS-STING pathway in HPV infected oropharynx cells, there are no reports of how this pathway may co-ordinate responses to these varied stimuli in oral cells. We have preliminary data showing activation of cGAS-STING as the replicative senescence program develops, and evidence of a role in the development of the senescence associated secretory phenotype (SASP). Experimental approach: A panel of primary oral keratinocytes and fibroblasts will be assessed for activation of the cGAS-STING pathway (both in monolayer and as engineered mucosa), under challenge with components of the oral microbiome (including isolated virulence factors and whole cells), replicative senescence and HPV infection. The project will encompass a wide range of molecular biological techniques including qPCR, western blotting, immunofluorescence (with high resolution microscopy) and ELISA. The effects of pharmacological inhibition of the pathway and knockout of key components by CAS9-CRISPR will be assessed in these cells under the same conditions. Key elements of the activation of the pathway and associated responses will be assessed in range of inflammatory, infective and neoplastic oral tissues by immunofluorescence/immunohistochemistry, relating this to the inflammatory response seen in tissues and clinical outcomes in neoplastic disease.

Funding Notes

Funding:
These studentships will be 42 months in duration, and include home fee and stipend at UKRI rate.

Eligibility:
Candidates must have a minimum of an upper second class honors degree (2:1)

References

Enquiries:
Interested candidates should in the first instance contact Prof Keith Hunter ([email protected])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Dentistry' as the department.

Deadline for applications is 5pm on Wednesday 29th January 2020. Late applications will not be accepted. Interviews are scheduled to be held on Tuesday 25th February 2020.

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