About the Project
Supervisors:
Dr Erin Greaves
Prof. Andrew Horne
Prof. Jeff Pollard
Background
Endometriosis is a chronic estrogen-dependent inflammatory condition that affects 1 in 10 women of reproductive age. It is associated with debilitating pelvic pain and infertility and has a huge adverse impact on health-related quality of life. Current therapies are limited to surgery or hormonal suppression. Women want new alternatives to current treatment options.
Endometriosis is the ectopic growth of the lining of the uterus (endometrium), typically on the lining of the pelvic cavity (peritoneum) as ‘endometriosis lesions’. The pain associated with endometriosis is believed to be a result of the growth of new small diameter nerve fibres, typical of sensory innervation, into the ectopic tissue(1).
In women with endometriosis the peritoneal cavity and lesions contain high numbers of activated macrophages(2). Macrophages are cells of the innate immune system and are found in all tissues. They regulate processes important in development, tissue homeostasis and repair processes as well as immunity(3). Signals from the local tissue environment determine the activation state and function of tissue resident macrophages that ultimately exhibit high transcriptional diversity depending on location(4-6). Macrophages also play a role in many disease states(7).
Macrophages and nerves are seen in close proximity in endometriosis lesions(8). We have recently shown that macrophages activated to mirror the lesion environment possess neurotrophic properties. These properties are dependent on estradiol-regulated expression of neurotrophins(9). We think macrophages may also activate sensory neurons innervating lesions thus contributing to pain in the disorder.
Hypothesis
The endometriosis-associated macrophage exhibits a characteristic neurogenic signature of factors with common up-stream regulatory molecules that can be inhibited to target endometriosis-associated pain.
Research aims
1. To explore the activation status and neurogenic signature of macrophages in endometriosis
2. Determine common regulatory molecules upstream of identified neurogenic genes
3. To use inhibitors of identified candidate genes or common regulatory molecules in a mouse model of endometriosis-associated pain
Research methodology
The student on this project will explore the activation status and neurogenic signature of human peripheral blood monocyte derived macrophages activated with peritoneal fluid or total protein supernatants from lesion biopsies taken from women with endometriosis. Methodologies will include multicolour flow cytometry and gene array analysis. The functional role of identified genes of interest will be followed up using in vitro models of neuronal outgrowth and activation(10, 11). Bioinformatics analysis will be used to determine common regulatory molecules upstream of identified genes that may represent potential targets for new therapies for endometriosis-associated pain. The student will explore the relevance of these targets using in vitro systems genetically modified using CRISPR/Cas9 technologies. Targets showing promise in in vitro systems will be explored using inhibitors in our novel mouse model of endometriosis(12). The efficacy of inhibitors in treating endometriosis-associated pain will be assessed using behavioural studies.
The project will provide training in a range of in vitro and in vivo modelling techniques in a highly translatable area of reproductive and inflammatory biology.
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.
www.crh.ed.ac.uk
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.
References
1. N. Tokushige, R. Markham, P. Russell, I. S. Fraser, Nerve fibres in peritoneal endometriosis. Hum Reprod 21, 3001-3007 (2006).
2. X. Cao, D. Yang, M. Song, A. Murphy, S. Parthasarathy, The presence of endometrial cells in the peritoneal cavity enhances monocyte recruitment and induces inflammatory cytokines in mice: implications for endometriosis. Fertil Steril 82 Suppl 3, 999-1007 (2004).
3. T. A. Wynn, A. Chawla, J. W. Pollard, Macrophage biology in development, homeostasis and disease. Nature 496, 445-455 (2013).
4. L. C. Davies, S. J. Jenkins, J. E. Allen, P. R. Taylor, Tissue-resident macrophages. Nat Immunol 14, 986-995 (2013).
5. E. L. Gautier, T. Shay, J. Miller, M. Greter, C. Jakubzick, S. Ivanov, J. Helft, A. Chow, K. G. Elpek, S. Gordonov, A. R. Mazloom, A. Ma'ayan, W. J. Chua, T. H. Hansen, S. J. Turley, M. Merad, G. J. Randolph, Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13, 1118-1128 (2012).
6. S. Gordon, P. R. Taylor, Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953-964 (2005).
7. J. W. Pollard, Trophic macrophages in development and disease. Nat Rev Immunol 9, 259-270 (2009).
8. L. V. Tran, N. Tokushige, M. Berbic, R. Markham, I. S. Fraser, Macrophages and nerve fibres in peritoneal endometriosis. Hum Reprod 24, 835-841 (2009).
9. E. Greaves, J. Temp, A. Esnal-Zufiurre, S. Mechsner, A. W. Horne, P. T. Saunders, Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis. Am J Pathol, (2015).
10. E. Greaves, F. Collins, A. Esnal, S. Giakoumelou, A. W. Horne, P. T. Saunders, Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3. Endocrinology, en20141086 (2014).
11. E. Greaves, K. Grieve, A. W. Horne, P. T. Saunders, Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis. J Clin Endocrinol Metab, jc20142282 (2014).
12. E. Greaves, F. L. Cousins, A. Murray, A. Esnal-Zufiaurre, A. Fassbender, A. W. Horne, P. T. Saunders, A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. Am J Pathol 184, 1930-1939 (2014).
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