Testosterone as a determinant of Western disorders in men and associated low-grade inflammation

3-Year PhD Studentship in Reproductive Health Sciences

Supervisors - Prof RM Sharpe, Prof A Rossi, Dr AJ Drake

Project - Testosterone as a determinant of Western disorders in men and associated low-grade inflammation

The Medical Research Council (MRC) Centre for Reproductive Health (MRC-CRH) conducts research into conditions that affect reproductive fitness and the health of male and female reproductive organs including infertility, endometriosis and premature birth. The Centre brings together scientists who have outstanding strengths in reproductive biology, stem cells, inflammation, development, hormonal disease and imaging. We provide a rich environment for training of clinical and non-clinical scientists and a vibrant programme of activities aimed at encouraging public engagement in science.

Three 3-year PhD Studentships will be available in September 2013 to outstanding science graduates wishing to pursue a career in Reproductive Health Sciences. The studentship will cover tuition fees at the UK/EU rate, a stipend (currently £13,726) with a rise each year to match inflation. This PhD Programme seeks to attract the best students from across the UK and EU to join our internationally recognised research community of Reproductive Health Scientists in Edinburgh. The Centre has a thriving postgraduate community of more than 30 MSc and PhD trainees who are mentored by a postgraduate studies committee.

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 relevant subject would be an advantage.

The Little France Campus

The Centre for Reproductive Health 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) and the Clinical Research Imaging Centre (CRIC) and the MRC Centre for Regenerative Medicine (CRM).

Background and aims: Low grade chronic inflammation occurs in several high incidence, age-related, ‘Western’ disorders in men - obesity, type 2 diabetes, liver and cardiovascular disorders. Men with these disorders have lowered testosterone levels associated with a pro-inflammatory cytokine blood profile. Testosterone levels decline with aging in men, in association with adverse metabolic and cardiovascular changes, that are exacerbated by visceral obesity; the latter is inversely related to testosterone levels in men. Moreover, three large studies have shown that testosterone levels in men have declined across age groups with more recent year of birth. Finally, fetal events that affect bodyweight at birth affect both testosterone levels in adulthood and the risk of developing ‘Western’ disorders. Therefore, testosterone, low grade inflammation and Western disorders are closely inter-related. What is unclear is the extent to which testosterone levels, whether in fetal life or adulthood, is the driver of the other health changes. This project aims to establish the extent to which testosterone is in the driving seat, and whether it might have therapeutic uses to reduce inflammation and Western disorders.

Hypothesis and main approaches of this project: This project will explore the hypothesis that experimental or diet/obesity-induced lowering of circulating testosterone levels in males results in pro-inflammatory changes in the circulation and in specific reproductive and non-reproductive organs that may predispose to development of chronic disease. It will explore if this is due to androgens per se or to disturbance of the androgen:oestrogen balance and will establish if restoration of normal testosterone and/or oestradiol levels is able to ameliorate the inflammatory profile. Additionally, the project will investigate the role that fetal programming may play in predisposing to androgen/oestrogen-mediated pro-inflammatory changes.
The project will use rodent models in which androgen and/or oestrogen levels/action and diet are experimentally manipulated at different life stages, and will establish if and when this leads to inflammatory changes (altered leucocyte numbers, levels of inflammatory markers) in reproductive (testis, epididymis, prostate) and/or non-reproductive tissues/samples (plasma, adipose tissue, liver, heart, pancreas), and whether such changes can be prevented/reversed by manipulation of testosterone or oestradiol levels or the testosterone:oestradiol ratio. The consequences for affected tissues would also be studied (e.g. fibrosis), as well as their reversibility. The cytokine/other pathways involved will be investigated to establish if inflammation in different organs has a common profile that might open other therapeutic possibilities.

Human health relevance of this project: The findings of this project would be of widespread health-relevance to men in relation to aging, diet and obesity and would add a new dimension to the well-established concept of the fetal programming of adult diseases in men. It will give fundamental new insight into the inter-relationships between sex hormone levels, cardiometabolic systems and inflammation in adulthood and the influence that fetal events may have on this. It will provide information on the likelihood of therapeutic intervention in such disorders.

How to Apply

For application, please submit a copy of:
• A curriculum vitae
• A ‘statement of purpose’ outlining your reasons for undertaking this programme of study and how you see it affecting your career plan, together with an indication of which project you are interested in (see list below)
• 3 academic references should email/send letters on your behalf to: [Email Address Removed]

PLEASE NOTE Applications sent directly to project supervisors may not be counted.

The closing date to apply for these studentships is Monday 11 March 2013.

If you have any questions regarding the programme please contact the programme secretary [Email Address Removed]