Our most recent translational projects

In our last round of Translational Research Project Grants we awarded funding to four projects across the UK, totalling almost £500,000.

Dr George Baillie, Universities of Glasgow and Strathclyde       
£142,586 24 month project

Development of novel drugs to protect the heart

Human life depends on the rhythmical beating of a healthy heart pumping blood around the body. Heart disease can result from the death of heart muscle cells following problems such as oxygen starvation, which occurs if the coronary arteries that supply blood to the heart muscle become blocked, or because of the pressure overload that results from having high blood pressure. As the heart is vital to life, the body makes small proteins to counteract heart cell death. One such protein, HSP20, is known to protect heart muscle cells from cell death following physical stress and has also been shown to improve the pumping ability of the heart. As the protective functions of HSP20 are only required in the heart during times of stress, HSP20 lies dormant in heart cells until needed. The body cleverly ‘switches on’ the protective effects of HSP20 under stressful conditions by slightly modifying the protein.

Recently, it was discovered that HSP20 binds to another protein called PDE4 which makes it more difficult for the body to switch on HSP20 when the heart is under strain. One way to get around this problem is to use a drug that blocks the activity of PDE4, allowing activation of HSP20 to happen. Such drugs do exist, however, they have never been given to patients as they would lead to intolerable side effects. This is because PDE4 has many vital functions outside the heart, for example, PDE4 is essential for memory and thought formation, as well as being important for normal food digestion. So although these drugs would target the PDE4 linked to HSP20, they would also affect the PDE4s in your brain and gut, resulting in serious problems such as vomiting and diarrhoea.

In this project, the research team will study the way in which HSP20 and PDE4 interact and develop ways of targeting the PDE4 that binds HSP20 through a completely new route. They plan to design new drugs that specifically dislodge the PDE4 that is bound to HSP20 without affecting the PDE4 elsewhere in the body. As a result, these new drugs should be safer and cause fewer side-effects. In fact, previous work by the team has resulted in the discovery of the very first disruptor of the HSP20-PDE4 complex, although it needs more development before it can be considered as a proper drug. They plan to build on this initial discovery by developing and testing more effective, powerful chemicals which break up the PDE4-HSP20 complex in order to allow the activation of HSP20.

Damage to the heart caused by diseases such as coronary artery disease and cardiac hypertrophy, causes serious health problems to patients and places a considerable burden on health services worldwide. By improving the activation of HSP20, this new class of drugs may reduce damage to the heart cells, preserving the pumping ability of the heart, delaying the onset of heart failure, and reducing deaths in patients with heart disease.

Dr Jane McEneny, Queen’s University Belfast               
£85,930 18 month project

SAA - a new test for coronary artery disease?

Coronary artery disease is caused by the build-up of fatty deposits within the blood vessels of the heart which can lead to angina and heart attacks and is a leading cause of death in Western societies. However, there is increasing evidence that long term inflammation also plays an important part in the disease process. One of the molecules that is released during inflammation is serum amyloid A (SAA), which also has the added disadvantage of binding to HDL – the so-called ‘good’ cholesterol. The protective role of HDL is well established and this binding between SAA and HDL means that HDL is less effective at removing excess cholesterol from the body and preventing atherosclerosis.

In this project, the team will assess the levels of SAA and SAA linked to HDL in blood samples taken from patients admitted to hospital with suspected cardiac chest pain. They will then see if these blood levels correlate with the degree of atherosclerosis as determined by non-invasive scanning of fatty deposits within the coronary arteries. In addition, the team will examine if and how the heart protective properties of HDL are altered by the presence of SAA.

Overall, the aim of this research is to determine whether levels of SAA or SAA linked to HDL can be used as a simple test for identifying patients with coronary artery disease. Better diagnosis would mean that treatment could be targeted to those that need it, earlier in the disease process, which would be of great benefit to patients with heart disease. 

Dr Vas Ponnambalam, University of Leeds               
£84,750 36 month project

Stimulating recovery from heart attacks using VEGF-A variants

Coronary artery disease is caused by the build-up of fatty deposits on the inside walls of the coronary artery which can rupture and cause a blood clot that blocks the artery, triggering a heart attack. There is a need for new treatments that can heal the damaged coronary artery following heart attacks and surgical treatment for coronary artery disease.

One possible candidate is VEGF-A which binds to receptors on the surfaces of endothelial cells lining the inside of the arteries. This triggers the repair of the endothelial cells and regeneration of the artery. However, the human VEGF-A gene is thought to code for at least seven different forms of the VEGF-A protein and the roles of each different version of VEGF-A in stimulating the endothelium to promote repair and regeneration of the blood vessels in cardiovascular disease are not known.

This research will test the idea that particular forms of VEGF-A can stimulate repair and regeneration of blood vessels. Using genetic engineering, the researchers will produce and purify different forms of VEGF-A in human cells and then test their effects on receptors and cellular responses in human endothelial cells. In addition, these VEGF-A proteins will be further studied by comparing their ability to promote repair of arteries in a laboratory model.

This project will help to identify VEGF-A variants that have the potential to stimulate the repair of damaged arteries after heart attack and which may lead to the development of better treatments for cardiovascular disease in the future.

Prof Annette Graham, Glasgow Caledonian University           
£90,407 24 month project

Finding new drugs to reduce arterial cholesterol levels

Coronary artery disease involves the accumulation of LDL - the so-called ‘bad’ cholesterol - in white blood cells within the fatty deposits which build up on the artery wall. The white blood cells involved in these events as called macrophage ‘foam cells’. The presence of HDL - the ‘good’ cholesterol - in the bloodstream can reverse this, enhancing removal of cholesterol from the body and reducing the risk of coronary artery disease. But at the moment, there are no effective treatments which can boost this pathway. Recent work by this team has shown that they can improve the protective effects of HDL by increasing the levels of a protein called TSPO, or by adding small molecules/drugs which increase the activity of this protein.

TSPO is widely distributed in the body and drugs which can activate TSPO are being developed as treatments for anxiety. Encouragingly, these drugs did not produce withdrawal symptoms or unwanted side effects in early clinical trials.

Using cells kept alive in tissue culture dishes, and cells stimulated to become foam cells, this research will test a range of different classes of TSPO-binding chemicals, including those being developed for the treatment of anxiety. This will allow the researchers to find out which classes of TSPO- binding chemicals are most effective at enhancing cholesterol removal from foam cells to HDL.

Despite the success of the statin drugs, which lower levels of ‘bad’ cholesterol in the bloodstream, we urgently need effective treatments which can reverse the build-up of fatty substances in the arteries. If successful, this work will highlight important new uses for TSPO-binding chemicals, stimulating further research into the benefits of these drugs in the treatment of cardiovascular disease and may lead to clinical trials in patients.

Prof Khalid Naseem, Hull York Medical School           
£74,805 36 month project

Regulation of platelet activity by blood fats

Blood platelets are a group of cells that clump together to form blood clots, ensuring that we stop bleeding after injury. However, in cardiovascular disease, platelets also form blood clots inside the blood vessels causing thrombosis which may lead to heart attacks and strokes.

We know that people at risk of heart disease often have increased levels of fat in their blood, and that raised fat concentrations may cause platelets to form clots more readily in the blood stream. Recent research by this team has revealed a new biochemical process which stimulates platelets to form clots and it is thought that this may be how increased fat in the blood causes clots to form.

In this project, the researchers will use platelets taken from the blood of healthy volunteers and also people at risk of heart disease, to study in detail the ways in which blood fats activate platelets. They will use a number of experimental methods to improve our understanding of the mechanisms of action of these blood fats.

Inappropriate platelet activity is closely linked with heart disease, stroke and thrombosis which are the leading causes of death in the UK. There is increasing evidence that the levels of fats in the blood are critical in increasing the risk of heart disease, so a better understanding of the effects of fats on platelets will increase our knowledge of their role in thrombosis. This information is crucial in order to help doctors understand the causes of abnormal platelet function in disease. Furthermore, this research will help to pave the way for the development of new medicines to prevent cardiovascular disease.