Exploring bias in platelet P2Y1 receptor signalling: host defence versus haemostasis.

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Blood contains cells to kill germs. In order to defend us against germs, they need to leave the bloodstream and travel through the inflamed tissue to reach the germs, engulf them and secrete materials that help kill them. The body does this via a protective mechanism called the inflammatory response. Sometimes this inflammatory response occurs inappropriately in diseases unrelated to infection, which then unfortunately causes self-inflicted harm to the body, for example in asthma, chronic obstructive pulmonary disease (COPD, mostly caused by smoking), or inflammation caused by sudden trauma. Previously, our research group have discovered that white blood cells called leukocytes require the help of yet another blood cell type, the platelets, to be able to migrate from the blood stream to sites of inflammation and infection. Platelets are best known for forming blood clots, thereby preventing us from bleeding to death every time we have an injury (this process is known as haemostasis), but because they also guide the white blood cells to reach inflamed organs as well as helping the white blood cells to fight and kill germs, they are also indispensable for our immune system. Yet, the processes of haemostasis and inflammation are distinct. The main aim of our research project here is to learn how platelets get activated in response to the protective process of inflammation, without affecting the essential process of haemostasis, because this might lead to excessive bleeding, or blood clots. Research into how platelets become activated during inflammation is important for basic science, but also because current medical treatments are just not good enough. We require better medicines - because 5.4 million people in the United Kingdom suffer from asthma, and 1.2 million suffer from COPD. Despite better management of patients, and the introduction of new drugs, 3 people die every day in the UK as a result of an asthma attack, 80 people die every day as a result of COPD, and people who have inflammation of the lungs associated with acute trauma or pneumonia have between a 20 and 50% death rate. If we can find new ways of modulate platelet activity at the site of inflammation, without affecting normal blood clotting, we might be able to create new medicines that improve the health of millions of people.Platelets express proteins called purinergic receptors that are important for switching platelets 'on' during blood clotting, but when certain types of purinergic receptors get switched 'on' in an inflammatory environment, they boost activity to help fight germs instead of forming blood clots. We will research how a particular purinergic receptor (P2Y1) works to control platelet activity during inflammation, compared to their function in blood clotting. To do this, we have assembled a team of scientists from within King's College London, with different areas of expertise (computer modellers, synthetic chemists, pharmacologists) to create new molecules that are designed to change P2Y1 function. Receptors change shape continuously, and depending on what shape they are, when activated, platelets will function differently based on the shape or conformation of the receptor. The new molecules will be designed to bind to P2Y1 when it is a particular shape. We hope to change selective functions of platelets necessary for inflammation, to fight infection, or for clotting of blood. Together, we will create a library of these molecules to be used as research tools (called 'biased' agonists-activation antagonists-blocking) after computer-aided modelling. We will measure the functions of platelets in the presence of these agonists and antagonists, and their effects on white blood cell activation, both in the test tube and in actual inflammation and infection. This research project will help us and other scientists understand exactly how P2Y1 on platelets works during inflammation compared to blood clotting.