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The Cellular Origin of Human Papillomavirus Associated Neoplasia

  • Full or part time
  • Application Deadline
    Wednesday, January 01, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Human Papillomaviruses (HPV) cause widespread asymptomatic infections in the general population, in addition to a range of cancers which occur at number of well defined epithelial sites. The most significant of these ’vulnerable’ epithelial sites is the cervical transformation zone, but HPVs also cause cancers at the anal transformation zone, the crypts of the tonsils, and the conjunctiva of the eye. Together, these viruses are responsible for around 6% of human cancers, and although there are effective prophylactic vaccines against some HPV types, there are currently no antiviral therapies available for the treatment of precancerous lesions.
The project will combine the analysis of HPV-infected clinical biopsies (the gold standard), with the use of tissue culture models, to investigate the mechanisms that these viruses use to disrupt normal epithelial homeostasis. Of particular interest will be the targets of the HPV E6 proteins, which are involved in signal transduction, cell density regulation, differentiation and delamination; the process that epithelial cells use to detach from the epithelial basal lamina. Competition experiments using fluorescently tagged epithelial cells expressing individual viral gene products or WT/mutant viral genomes, will be used to map HPV homeostasis modulation. In particular, the study will examine the columnar and stratified cells that make up the transitional epithelial sites where HPV causes cancer, and the regulatory processes that control these epithelial sites. Single cell sequencing, CRISPR methodologies and organoid culture methods will be amongst the cell biology methodologies used during the study.

Funding Notes

Funding* will cover the student’s stipend at the current Research Council rate and University Fees. The studentships will be funded for three years in the first instance subject to eligibility**, with the possibility of additional funding in the fourth year depending on circumstances.

**The studentships are available to students who qualify for Home/EU fees

Applications from ineligible candidates will not be considered.

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References

1. Roles for E1-independent replication and E6-mediated p53 degradation during low-risk and high-risk human papillomavirus genome maintenance. (2019) Murakami I, Egawa N, Griffin H, Yin W, Kranjec C, Nakahara T, Kiyono T, Doorbar J. PLoS Pathog. 2019 May 13;15(5): PMID:31083694

2. Doorbar J, Griffin H. (2019) Refining our understanding of cervical neoplasia and its cellular origins. Papillomavirus Res. 2019 Jun;7:176-179. PMID: 30974183

3. Griffin H, Singh Mudhar H, Rundle P, Shiraz A, Mahmood R, Egawa N, Quint W, Rennie IG, Doorbar J. (2019) Human papillomavirus type 16 causes a defined subset of conjunctival in situ squamous cell carcinomas. Mod Pathol

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