Alzheimers disease is the commonest form of dementia that affects a large proportion of the elderly population of the UK. Many other people are affected through knowing a family member or friend who has this debilitating disease. Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are much rarer but have received much attention in recent years because of the still unknown number of people in the UK infected following the epidemic of bovine spongiform encephalopathy (BSE) (mad cow disease). Both these brain diseases are fatal and, as yet, there are no cures for either disease. We have noticed similarities in the way that brain cells regulate the processing of key proteins that cause Alzheimers and prion diseases. The aim of this proposal is to investigate these processes in cells and animals, as well as in post-mortem brain tissue from Alzheimers patients. The results from our work will help us understand how these diseases develop and may aid in the identification of new treatments.

Certain viruses have been shown, in the laboratory, to be able to kill cancer cells. These viruses are not normally damaging to humans and don‘t generally cause significant illnesses. Some cancer cells have lost the ability to eradicate viruses in the way that healthy cells can, so that these viruses can be used to target and selectively kill cancer cells in patients. We are trying to improve the effectiveness of this approach by studying different viruses, and by combining the viruses with cells from the body‘s own immune system which themselves can attack cancer. Combining cell and viral therapy for cancer is an exciting new approach to cancer therapy. Critically, this research is focused on testing cells and viruses using human reagents, including tumour cells freshly resected from patients; this ensures that our work is of maximum relevance to the disease as seen in patients, and helps rapid translation of our findings into early clinical trials. We‘re specifically looking at melanoma; an aggressive form of skin cancer that kills thousands of people, particularly young people, each year, and for which there is little effective treatment. We hope our research will also benefit other cancers too.

Cardiac hypertrophy is a disease in which the heart is enlarged, and is associated with an increased risk of ventricular fibrillation, an often fatal arrhythmia where the normal electrical and mechanical activity of the heart is disturbed and the heart stops pumping blood. The aim of this project is to develop computer models of the heart that can be used to investigate the causes of ventricular fibrillation during hypertrophy, and potential ways of reducing the risk of such arrhythmias occurring. The shape and structure of the heart in both normal and hypertrophic conditions will be determined using a technique known as diffusion tensor magnetic resonance imaging (DT-MRI). As little is known about how the structure of the heart varies between individuals, or from species to species, libraries of heart shape and structure will be produced that will allow comparisons to be made. Using this information, along with more data obtained using the techniques of histology and immunohistochemisrty, mathematical descriptions of the heart‘s electrical and mechanical activity will then be developed. The resulting electromechanical models will contract and change shape, something that current models do not do. These models will then be used to examine ventricular fibrillation in the hypertrophied heart.

In Alzheimer s disease there is a build-up of protein in the brain that is thought to cause the death of nerve cells. We have found that this protein, named amyloid beta protein (Abeta), causes changes in the electrical activity of nerve cells when in a form that is not usually associated with the disease. In fact, we suspect that this may be a normal function of the protein. We believe that during the disease process Abeta] may lose its ability to alter electrical activity and this leads to death of nerve cells. This idea needs to be tested and to do this we will measure the effects of normal Abeta and abnormal Abeta on the electrical activity of individual nerve cells. In separate experiments we will also be able to track changes in levels of proteins involved in causing electrical activity in nerve cells (ion channels), and view their position within the nerve cells. This will give us more detailed information on the changes that occur and their consequences during the disease. Because we believe that changes in protein will result in nerve cell death we will also look at how ion channel activity changes in nerve cells that are just beginning to enter the cell death death process. This will allow us to directly measure differences between the electrical activity of nerve cells that are healthy and those that are not. The information gained from these experiments will tell us how important changes in electrical activity in the brain of Alzheimer s disease patients are in causing the death of the nerve cells. This is vitally important since, unlike almost all other cell types, nerve cells do not divide and replace themselves. If we can prevent the cell death caused by Abeta we may therefore be able to slow or halt the progression of Alzheimer s disease.