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.

Professor Jules Hancox, University of Bristol, with Professor Henggui Zhang, University of Manchester
£99,834    24 month project

Understanding drug-induced cardiac arrhythmia risk

Disturbances to the heart's normal electrical rhythm are called 'arrhythmias'. Depending on the severity and type, cardiac arrhythmias can lessen the quality or length of a person’s life.  In some cases, it can even cause sudden death. The electrical activity of the heart depends on the co-ordinated opening and closing of tiny proteins in the membrane of each heart muscle cell, called 'ion channels'. The flow of ions through these channels is responsible for the spread of the electrical signal which in turn initiates the pumping action of the heart.

Sometimes patients taking drugs to treat medical conditions suffer adverse cardiac side effects - the heart reacts to the drug by producing a cardiac arrhythmia that can either spontaneously get better, or degenerate into a fatal rhythm disturbance. However, little is known about why some people are more at risk of harmful cardiac side effects of drugs than others.

One particular ion channel in the heart which is important to arrhythmia risk is called 'hERG'. By allowing potassium ions to leave heart cells, hERG channels play an important role in controlling the normal electrical activity of the heart’s pumping chambers. Many drugs that cause harmful cardiac side-effects do so by altering the function of hERG channels. This project seeks to understand whether mutations in a particular gene called ‘KCNE1’ may affect hERG channels, and hence provide an explanation about why some people are particularly vulnerable to drug-induced arrhythmia.

This laboratory-based project will produce and compare individual cells containing hERG and normal or mutant KCNE1 protein. The researchers will use methods to record the electrical activity of these cells, to investigate drug effects and to carry out computer simulations. This will allow them to see in detail how mutations in the gene alter hERG channel function and to examine the ability of antiarrhythmic drugs to modify the channel's activity. This knowledge may lead to a better understanding of how the normal electrical activity of the heart is adversely affected by drugs in some people but not in others. Ultimately, this may help tailor drug treatments so that susceptible individuals can avoid harmful cardiac side-effects.

Dr Paul Kingston, University of Manchester
£115,346    24 month project

Preventing complications arising from the treatment of heart disease

Angina and heart attacks are caused by narrowing of the coronary arteries that supply the heart muscle with blood. Angioplasty is often used to widen the narrowed part and usually a small metal scaffold - called a stent - is left in place to keep the vessel open. However, there is a risk of the stented artery renarrowing because of a process similar to scar formation.

In recent years, ‘drug-eluting’ stents have become available that are coated with drugs which are effective at preventing renarrowing. The drugs work by preventing the cells of the blood vessel wall from multiplying and producing scar-like tissue. However, they also appear to prevent normal healing processes, increasing the risk of blood clots forming in the stented blood vessels which may cause a heart attack. Therefore, patients must take expensive blood-thinning medications, with the associated risk of bleeding problems, for prolonged periods of time.

This research team is developing a new type of treatment that can be coated onto a stent. It has been shown to reduce the effects that cause renarrowing without stopping the cells of the artery wall from multiplying. This pioneering ‘gene therapy’ technique works by delivering small pieces of DNA from the stent to the cells of the blood vessel wall. The DNA contains a gene that is used by the vessel wall cells to produce a protein which reduces the formation of scar-like tissue in the artery. The team has spent some years developing suitable ways of delivering DNA from stents to the cells of the vessel wall and modifying the gene to optimise its benefits.

In this project, different versions of the treatment will be tested in left-over vein samples from patients undergoing heart bypass surgery. When the best combination of gene and delivery system has been established, the benefits will then be tested further.

It is hoped that this new treatment will prevent renarrowing of stented arteries, but will not increase the risk of blood clots associated with currently-used drug-eluting stents. If so, this would have the potential to benefit thousands of patients with heart disease every year.

Dr Paul Barton, Imperial College London
£113,140    24 month project

Heart failure recovery

Despite recent medical advances, heart failure remains a serious problem. In severe cases, there are few treatment options and the outlook for these patients is poor. While transplantation offers effective treatment for the few who are lucky enough to receive a donor organ, there is an urgent need to find new treatments.

One option is the use of mechanical support for the failing heart and this can be achieved by implanting a left ventricular assist device (LVAD) - a mechanical pump which takes over the heart’s work of pumping blood around the body. LVADs are most often used to help severely ill patients until they receive a heart transplant.

This research team has developed a new treatment whereby patients on LVAD support also received heart failure therapy drugs. This has led them to find that with the right drug combination certain groups of patients actually get better. Over time their hearts started to work well again and following treatment, it was possible to remove the LVAD and for them to return to normal life. However, little is known about how recovery of the heart occurs in these patients.

This unique study will build on the research team’s HRUK-funded project which began in early 2010. The researchers will carry out a detailed analysis of substances circulating in the blood, before, during and after treatment. Tests will include measuring levels of biological markers of recovery from heart failure. This information, combined with a genetic analysis of heart muscle samples, will give a better understanding of the changes taking place in the patients. By examining the differences between patients that recover and those that do not, it is expected that the study will improve our understanding of heart failure. This will pave the way for tests to determine which patients are likely to benefit from this treatment and may also contribute to the development of future drug treatments to reverse heart failure.

Dr Fredrik Karpe, University of Oxford
£149,997    30.5 month project

Understanding the link between obesity and cardiovascular disease

Obesity is a well-known risk factor for cardiovascular disease but the reasons for the link between the two are poorly understood.

‘G-protein coupled receptors’ (GPCRs) are found on the surface of most, if not all, cells in the human body. They are involved in cell signalling - a complex communication system which controls cellular activities. These receptors are very important as they are central to the regulation of most physiological functions in the human body. This project will look at the key role GPCRs play in both regulating blood flow and how fat is stored and released from fat deposits - to further our understanding of the link between obesity and cardiovascular disease.

Fat is transported to and from fat deposits, via the bloodstream, and the rate of blood flow through different fat deposits is important in controlling of levels of circulating blood fats. As fat accumulates in the body, the tissue changes the way it functions making the regulation of fat storage, and release, and flow of blood through the fat tissue less well controlled. Therefore part of this research will focus on the signalling that happens in the fat tissue through GPCRs, by studying fatty tissue biopsy samples from both lean and obese volunteers.

The regulation of blood flow is also partly controlled by GPCRs on the endothelium – the layer of cells that lines the blood vessels. The endothelium is very important in controlling the blood flow but this ability is often lost in obesity, which is why the study will also examine human endothelial cell samples.

By comparing the abundance of GPCRs in both endothelial cells and fat tissue, from lean and obese individuals, it will be possible to pinpoint which GPCRs might be involved in signalling changes which can lead to cardiovascular disease.

In a pilot study, the research team has already identified a number of GPCRs whose abundance is altered in obese individuals and in this project they expect to identify the ways other GPCRs work. GPCRs are the targets of many modern medicines and in the long term, this project may lead to new medicines to target them for the prevention of cardiovascular disease.