The Role of Cathelicidin in In Utero Inflammatory responses

Project Background:
Preterm birth, defined as delivery before 37 weeks of gestation, remains a major public health problem. It affects 11.1% of pregnancies worldwide, is the single biggest cause of neonatal mortality and in survivors negatively impacts health throughout life 1. Intrauterine infection is a key cause of preterm birth and is estimated to be present in up to 40% of spontaneous preterm deliveries. Infection is particularly associated with early preterm birth, and is thought to result from bacteria ascending from the lower genital tract into the uterus (1). Intrauterine infection triggers an inflammatory response in the fetal membranes and the placenta, with production of host defence peptides, cytokines and chemokines. Prostaglandin production is increased in the amnion and decidua, which contribute to the initiation of labour. Intrauterine infection also causes a fetal inflammatory response, and that this contributes to intrauterine inflammation and preterm labour. It is likely that the fetal lung principally drives this, but the fetal skin also contributes (2).

Despite the clear causal link between infection, preterm labour and fetal damage, antibiotic therapies have been largely disappointing in preventing preterm labour and morbidity 2. It is likely that therapies need to suppress not only infection, but also resultant inflammation. Inflammatory modulators in combination with antimicrobials show promise as potential strategies to improve outcomes in preterm birth (3).

Host defence peptides (HDP) are small cationic peptides that have both antimicrobial and inflammomodulatory activities. The two major families of mammalian HDP are defensins and cathelicidins. These peptides are produced by epithelial and inflammatory cells, and may have key functions in maintaining pregnancy. As such they make attractive therapeutic targets for the prevention of preterm labour and resultant complications. They may have key functions in maintaining pregnancy (4,5).

The aim of this project is to investigate the role of the HDP cathelicidin in the protection against infection and inflammation in pregnancy, and investigate its potential to be developed as a therapeutic agent to protect against infection induced preterm labour. You will use mouse models of preterm labour (6) and human tissues to study the production of HDP and elucidate their function. Specific questions will be: What are the immunomodulatory functions and mechanisms of HDP in pregnancy? Is cathelicidin involved in the onset of inflammatory preterm labour in a mouse model? Can modulation of cathelicidin alter outcomes in foetuses born preterm?

Based in the MRC Centre for Reproductive Health you will be co-supervised by investigators based in the MRC Centre for Inflammatory Research. Full training will be given in experimental design, student supervision and teaching, data analysis and data presentation and publication. The specific techniques involved in this project include working with animal experimental models, assays, quantification and localisation of RNA and protein and imaging. These techniques are well established within the laboratory giving a very high chance of early success and publication. There is an excellent track record for PhD training and success within the laboratory.

The Little France Campus
The 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 (http://www.ed.ac.uk/schools-departments/medicine-vet-medicine/about/little-france). The 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).

www.tommys.org
www.crh.ed.ac.uk
www.cir.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. Applicants must be able to meet the minimum requirements as set out through the application link. Please use the details above for Project title, Research Proposal and Supervisor details.

Application deadline 5pm, 3 August 2015.
Interviews are expected to take place on 12 August 2015, the successful applicant beginning studies in September/October 2015.