Mechanisms of endometrial repair during menstruation.
Supervisors: Hilary Critchley (MRC CRH); Jacqueline Maybin (MRC CRH); Sarah Walmsley (MRC CIR)
The human endometrium is a dynamic sex steroid target tissue that undergoes cyclical “injury and repair/remodelling” in response to sequential exposure to sex steroid hormones (oestrogen and progesterone; P) and P-withdrawal. t is an excellent “physiological” model for studying tissue regeneration and repair. Vasoconstriction within the endometrium results in a transient hypoxic episode in the luminal portion (upper layer) of the endometrium during shedding and subsequent scar-free regeneration. This hypoxic episode stabilises the master regulator of the hypoxic response in cells, hypoxia-inducible factor (HIF) via inhibition of prolyl hydroxylase (PHD) enzymes.
Endometrial leukocytes (e.g. neutrophils) are also involved in the initial inflammatory response at menstruation and are required for efficient repair. Neutrophils are themselves adapted to function at poorly oxygenated sites of inflammation, with hypoxia a key regulator of their functional longevity. The regulatory mechanisms by which endometrial cells and neutrophils co-ordinate a tissue repair processes, and the importance of hypoxia in regulating this physiological response, are not well understood.
Uterine pathologies such as heavy menstrual bleeding (HMB) are common and have huge impact on women’s quality of life, imposing a major burden on health care systems. The causes remain undefined. Recent evidence suggests that an altered inflammatory response during menses and/or aberrant hypoxia may cause HMB.
Aims and Hypothesis:
This project aims to determine the relative importance of HIF/hypoxia in regulating leukocytes during menses. Hypothesis: Hypoxic regulation of leukocyte function is necessary for efficient endometrial function and repair at menstruation, with disordered activity resulting in HMB.
1. Are endometrial leukocytes dependent on hypoxia/HIF for efficient function during menstruation?
• Myeloid vs global endometrial HIF deficiency in a mouse model of simulated menstruation will determine impact on menses/endometrial repair
• Use of a model with and without hypoxia at menses will determine the role of hypoxia in endometrial leukocyte number/function.
2. What is the phentoype of endometrial leukocyte expression of HIF/PHD pathway members in uterine tissue samples from women with normal and heavy menstruation?
• Investigation of well-characterised human uterine tissue samples from women with objectively measured normal and heavy menstruation, thereby providing translational relevance of murine studies.
Techniques will include animal surgery, descriptive studies of gene and protein expression and may be extended to include functional studies on isolated component cell types of endometrium (e.g. epithelial; stroma; immune cell and endothelial). Cellular and molecular techniques will include real-time PCR mRNA analysis, immunohistochemistry, cell-culture of endometrial component cells, including gene silencing; and other molecular techniques as appropriate. An understanding will be gained of the ethical considerations of animal work and working with human tissues, including data governance considerations.
Laboratory support: provided at technical and post-doctoral level
The Little France Campus
The MRC Centre for Reproductive Health (CRH) is located on the ground floor of the Queen’s Medical Research Institute on the University of Edinburgh’s Medical Campus at Little France. The MRC CRH enjoys close collaborative links with the other Centres on the Little France Campus including the MRC Centre for Inflammation Research (MRC-CIR); the British Heart Foundation Centre of Excellence in Cardiovascular Science (BHF-CVS), the Clinical Research Imaging Centre (CRIC) and the MRC Centre for Regenerative Medicine (CRM). The campus has a thriving postgraduate community.
Applicants are expected to have a good honours degree in the sciences (biological, chemical or physical), at least UK level of 2.1 or the equivalent from non-UK universities. A Master’s degree in a relevant subject would be an advantage.
Please submit a CV through the Admissions Enquiries form below.
A ‘statement of purpose’/personal statement and details of 3 academic referees will also be requested.
Application deadline 15 February 2016.
Interviews are expected to take place during early March 2016, the successful applicant beginning studies in September/October 2016, providing funding has been secured.
The 3 year MRC funded studentships are open to outstanding UK science graduates wishing to pursue a career in Reproductive Health. The studentship will cover fees at the UK/EU rate and a minimum stipend as directed by the MRC.
This research project will be in direct competition with 7 other projects currently on offer at the MRC-CRH. Usually the project with the best applicant/s will be awarded the funding. The funding is available to UK graduates who can demonstrate ordinary residence in the UK as defined at through the link below.
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