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Exploring the origins and activation dynamics of the endometriosis-associated macrophage in a novel mouse model

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  • Full or part time
    Dr Greaves
    Prof Horne
  • Application Deadline
    No more applications being accepted
  • Awaiting Funding Decision/Possible External Funding
    Awaiting Funding Decision/Possible External Funding

Project Description

Supervisors:
Dr Erin Greaves
Prof. Andrew Horne
Prof. Jeff Pollard

Background
Endometriosis is a chronic 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 fragments of endometrium (lining of the uterus), typically on the lining of the pelvic cavity (peritoneum) as ‘endometriosis lesions’. This ectopic tissue is disseminated into the pelvic cavity via the phenomenon of retrograde menstruation. We have developed a novel mouse model of endometriosis that uses donor mouse menstrual endometrial tissue that is transplanted into recipient mice, lesions form that phenocopy those seen in patients(1).

Macrophages are found in all tissues and regulate processes important in development, tissue homeostasis, repair and immunity. Tissue macrophages from different locations have high transcriptional diversity demonstrating that signals from the local tissue environment determine their phenotype and function(2-4). Macrophages play a role in many disease states. In women with endometriosis the peritoneal cavity and lesions contain high numbers of activated macrophages(5) that are thought to play a critical role in the survival of lesions(6, 7).

Recently, mouse studies have revealed that tissue-resident macrophages are determined in embryonic life, they persist throughout life and perform tissue-specific functions(8). These cells are independent from those monocytes / macrophages that are recruited into tissues from the blood stream during inflammation (elicited macrophages). Our previous work in our endometriosis model has demonstrated that lesion-resident macrophages originate from both the ‘donor’ endometrium and from the ‘recipient’ suggesting the presence of both tissue-resident and elicited macrophages. Current literature suggests that both pro-repair(6) and pro-inflammatory(9) macrophages exist in endometriosis, again supporting different origins for the lesion-resident macrophages but also suggesting that pro-inflammatory elicited macrophages may be re-programmed upon entry to lesions.

Hypothesis
Endometriosis-associated macrophages have different origins and exhibit changes in activation status that are disease specific.

Research aims
1. To determine the origin of macrophages in endometriosis lesions
2. To explore the activation status and dynamics of macrophages in endometriosis lesions
3. To explore possible macrophage recruiting and activating factors in endometriosis lesions

Research Methodology
In this project the student will use genetically modified mice to explore the contribution of elicited macrophages and tissue-resident macrophages in endometriosis lesions. Macrophage trafficking will be visualised using intra-vital confocal imaging. The student will explore the activation dynamics of infiltrating monocytes in the mouse model using flow cytometry and immunofluorescence. This will be complemented using in vitro and ex vivo experiments on human macrophages and tissue biopsies recovered from endometriosis patients. Factors that recruit and activate macrophages in endometriosis lesions will be investigated using gene / protein arrays and small molecule inhibitors in in vitro and in vivo models.


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.

How to apply?
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.

Funding Notes

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.
www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/

References

1. 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).
2. L. C. Davies, S. J. Jenkins, J. E. Allen, P. R. Taylor, Tissue-resident macrophages. Nat Immunol 14, 986-995 (2013).
3. 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).
4. S. Gordon, P. R. Taylor, Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953-964 (2005).
5. 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).
6. A. Capobianco, A. Monno, L. Cottone, M. A. Venneri, D. Biziato, F. Di Puppo, S. Ferrari, M. De Palma, A. A. Manfredi, P. Rovere-Querini, Proangiogenic Tie2(+) macrophages infiltrate human and murine endometriotic lesions and dictate their growth in a mouse model of the disease. Am J Pathol 179, 2651-2659 (2011).
7. A. Capobianco, P. Rovere-Querini, Endometriosis, a disease of the macrophage. Front Immunol 4, 9 (2013).
8. C. Schulz, E. Gomez Perdiguero, L. Chorro, H. Szabo-Rogers, N. Cagnard, K. Kierdorf, M. Prinz, B. Wu, S. E. Jacobsen, J. W. Pollard, J. Frampton, K. J. Liu, F. Geissmann, A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86-90 (2012).
9. M. T. Beste, N. Pfaffle-Doyle, E. A. Prentice, S. N. Morris, D. A. Lauffenburger, K. B. Isaacson, L. G. Griffith, Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Science translational medicine 6, 222ra216 (2014).

How good is research at University of Edinburgh in Clinical Medicine?

FTE Category A staff submitted: 206.93

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