The influence of metabolic disturbances on platelet function, thrombosis and vascular inflammation

Rationale:  People with thrombotic disease are more prone to form unwanted blood clots inside their blood vessels leading to heart attacks and strokes. Thrombosis is caused by a group of small cells called platelets, which when we cut ourselves, stick together to form a clot and stop us from bleeding. It is thought that the unwanted clots are caused by increased levels of fat and sugar in our blood that make the platelets stickier than normal. However, the mechanisms by which fat and sugar induce platelet-rich clots remains unclear.
 
Plan of work and impact of our studies: Our work is designed to identify proteins in platelets that promote thrombosis and involves using genetically modified mice where key proteins have been either deleted (knocked out) or inserted (knocked in). We sometimes feed the mice altered diets or administer chemicals that replicate dietary imbalances found in humans. Our laboratory then uses a number of specialist techniques that allow us to test how these proteins affect thrombosis. We first take blood from mice and examine platelet function and thrombosis in systems that mimic conditions found inside the body. If these experiments suggest that a protein could promote thrombosis, we will progress experiments to examine how this is influenced by metabolic imbalances in the blood. If we can identify novel proteins that promote platelet activation in mice we may be able to produce new and more effective medications to control thrombosis in humans.
 
Animal welfare: This work relies on the use of animals because of the distinct biology of platelets.  Unlike many cells there are still no effective methods for growing platelets in culture, meaning that the cells need to be harvested from fresh blood for each experiment.  Nevertheless, the welfare of the mice is an important part of our experimental planning. In order to reduce the numbers of mice we have a clear stop-go point that ensures that mice do not undergo unnecessary procedures. Where procedures on live mice are required, the mice are anaesthetised and killed humanely without waking up thereby minimising suffering. The dietary manipulation uses well established diets that cause short term and mild metabolic imbalances. Hence the programme is designed to identify proteins that promote disorders that have a significant burden on the health of the nation while minimising both animal numbers and their use in severe protocols.

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