UK : Newcastle University PhD Studentship

Influence of Telomere Length and Statins on Lymphocyte Growth Kinetics in Patients with Coronary Heart Disease

Institute of Human Genetics

Reference Code: IHG70

Supervisor (s): Professor Ioakim Spyridopoulos, Professor of Cardiovascular Gerontology
Institute: Institute of Human Genetics
Duration: 3 years, full time
Sponsor: Faculty of Medical Sciences, Newcastle University

Background
Telomerase is a DNA polymerase that elongates the ends of chromosomes, which are formed by TTAGGG DNA repeats called telomeres. Telomeres are widely regarded as the internal biological clock of a living organism, and shorten by a few base pairs with every cell division. In addition, they are also crucial to maintaining chromosomal integrity. Overexpression or endogenously active telomerase in stem cells can counteract replicative telomere shortening. In vitro, telomere shortening can be accelerated by either loss of telomere capping proteins (i.e. TRF2), oxidative stress, or DNA damage, each leading to premature senescence. Age-related pathologies with short telomeres include infertility, impaired wound-healing and liver cirrhosis. Individuals with agecorrected shortage of leukocyte telomeres have a significantly higher risk of developing coronary heart disease or of dying from cardiovascular and infectious disease. Male individuals with shorter telomere length have an increased risk of developing coronary heart disease (CHD). This telomere-attributed risk is completely attenuated by treatment with pravastatin, an inhibitor of the HMG-CoA reductase.

Plan
Unexpected results from animal experiments have shown that critically short telomeres in the absence of telomerase activity lead to restricted atheroma progression, most likely due to impaired proliferation of both, lymphocytes and macrophages, an important step in atherosclerosis development. Statins have also been shown to inhibit lymphocyte proliferation in vitro via modification of the mevalonate pathway and hereby increase of isoprenoid intermediates. We have found previously in patients with CHD telomere shortening in the lymphocyte population to be far more pronounced than in myeloid cells. We have also generated pilot data showing that atorvastatin inhibits the enzyme telomerase in human lymphocytes. The goal of this study is to a) retrieve evidence from patients with CHD whether statin therapy attenuates telomerase activity in peripheral blood lymphocytes in vivo, b) influences in vitro growth kinetics of these cells, c) investigate a potential link between growth kinetics, oxidative stress and telomere length, and d) analyse the mechanism of telomerase-inhibition by statins in vitro.

Experimental Approach
A. In vivo study

1. Longitudinal study of 50 statin-naïve patients with stable coronary heart disease.
2. Isolation of lymphocyte subpopulations by FACS sorting.
3. Surface staining.
4. Measurement of telomere length by Flow-FISH.
5. Measurement of telomerase activity and oxidative stress in lymphocytes.
6. Determination of growth-kinetics in cultured lymphocytes.

B. In vitro experiments

1. Modulation of telomerase activity by statins.
2. Akt/Foxo3a pathway and telomerase inhibition
3. Dependence of statin-effect on interferon-γ.
4. Measurement of telomere length in long-term cultures.

Person Specification
Applicants should have a Master’s degree (MSc or MRes), or equivalent in a relevant subject. Applicants whose first language is not English must have IELTS 6.5, or equivalent.

Value of the Award and Eligibility
This studentship covers fees at the UK/EU rate and an annual stipend of £12,940. International students may apply but will be required to source additional funding to cover the cost of their fees.

How to Apply
To apply for the studentship please complete the University’s online postgraduate application form, quoting the reference number IHG70. You should select ‘PhD in the Faculty of Medical Sciences (full time) – Human Genetics’ and attach a CV and covering letter.

Early application is advised as this position will only be available until a suitable candidate is found.

Further Information
Please contact Professor Ioakim Spyridopoulos, ioakim.spyridopoulos@ncl.ac.uk, for further details.