LICAMM The role of platelet dysfunction in promoting diabetic thrombo-inflammation.

Summary

Insulin resistance (IR), defined as resistance to insulin-stimulated glucose uptake, is a common precursor to both diabetes and associated vascular disease. IR is a multi-system disorder that is characterised by multiple metabolic and cellular alterations including atherogenic dyslipidemia, glucose intolerance and inflammation. In subjects with Type 2 diabetes (T2D) immune cells are transformed into a proinflammatory state that is associated with increased production of the cytokine interleukin 1b (IL-1b). 1 This proinflammatory cytokine is deposited in the vascular wall of atherosclerotic coronary arteries in humans and promotes several atheroclertoic processes in mice 2. These observations are the basis for a large scale clinical trial (CANTOS) targeting IL-1b with a human monoclonal antibody to reduce of the incidence of myocardial infarction.

Subjects with type 2 diabetes (T2D) have increased circulating levels of platelet-monocyte complexes that are known to drive vascular inflammation. 3 However, the precise role of platelet-mediated inflammation in T2D is unclear. Recent evidence suggests platelet driven inflammation proceeds through the ability to modify their proteome. Experiments performed in vitro demonstrate that platelets produce proteins that potentially influence the thromboinflammatory process including IL-1b. 4 In immune cells IL-1bis generated through the activation of inflammasomes, multimeric protein signaling complexes that trigger the activation of caspase-1 and maturation of IL-1b. The most widely characterised of these is the NOD-like receptor (NLR)P3 inflammasome and is proposed to be expressed in human platelets 5.

In this project you will establish the molecular mechanisms that facilitate platelet IL-1b production and determine if the capacity for platelet IL-1bsynthesis is elevated in patients with T2D. The project provides excellent opportunity to gain training in a wide range of cell and molecular biology techniques, including immunoblotting, immunoprecipitation, flow cytometry, immunofluorescence, super-resolution microscopy and in vivo thrombosis assays.

References:

Lee, H.-M. et al. Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes. Diabetes 62, 194–204 (2013).

Kaptoge, S. et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 35, 578–589 (2014).

Ferroni, P., Basili, S., Falco, A. & Davì, G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2, 1282–1291 (2004).

Lindemann, S. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis. J Cell Biology 154, 485–490 (2001).

Abderrazak, A. et al. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biology 4, 296–307 (2015).

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.