Proteins control most of the important reactions carried out within cells. It is widely recognised that the timely removal of proteins by protein destruction is easily as important as making proteins at the correct time. In humans when this process goes wrong the results are catastrophic for the individual causing a wide range of debilitating diseases such as cancer, Alzheimers and Parkinsons disease. Proteins are targeted for destruction by being marked by the addition of a ubiquitin chain. The chain acts as flag, which is recognised by the cell and the protein rapidly turned over by the 26S proteasome, which acts as a protein shredder. We study how the ubiquitin flag is recognised by the cell. Previously, we have identified a number of flag recognition proteins. We propose to carry out a number of experiments to investigate how these flag recognition proteins can interact with the flag adding machinery of the cell and then present the marked proteins for degradation by the 26S proteasome.||Recently, another protein flag called Nedd8 has been shown to be added to many different proteins. The function of Nedd8 addition to proteins is at present unclear but it is known that it does not target them for destruction. But as a substantial number of proteins seem to be modified in this way it seems that modification by this protein will have important implications for intracellular regulation. We propose to identify the different proteins modified by this protein flag and investigate how modification alters the properties of the protein.

Death from respiratory disease in the UK is twice the EU average. Illnesses such as lung cancer, asthma, pneumonia and chronic obstructive pulmonary disease are now killing more people in the UK than coronary heart disease. Cystic fibrosis is an inherited condition and results in premature death from lung disease as a result of repeated airway infections. The predominance of multi resistance superbugs makes the illness more difficult to treat and limits the quality of life of affected individuals.||Recently I have identified several naturally occurring small antibiotic molecule that are effective at killing several important superbugs. I wish to understand how this molecule kills bacteria and whether this will help the design of new antibiotics for use in the clinic.||I am also interested in how these host defence peptides are involved in inflammation and what function they have in addition to being antimicrobials.

Many different factors influence the health of individuals, be they domestic animals or humans. These factors can broadly be categorised as either genetic or environmental. Thus the genes inherited from parents and the environments encountered during life are paramount in determining health status as one ages. These factors may also interact, such that individuals with one genetic make-up may react well to a particular environment, whereas a different genetic make-up may react badly. Where a substantial proportion of the genetic and environmental factors can be identified it is possible to provide accurate predictions of individuals' health as they age. Using such genetic information in prediction has great potential as it can be measured early in life and is unchanging throughout life. So there is the potential to be aware in advance of the environmental conditions that will optimise the future health of individuals. Such prediction is potentially a powerful tool to promote healthy ageing and wellbeing in both humans and companion animals, as it allows increasing efficiency of interventions, such as recommended diets or even drug treatments, and the targeting interventions towards those individuals who will most benefit. Combining genetic and environmental information is therefore the natural way to proceed when predicting how animals or humans will age and this project is concerned with developing accurate mathematical and statistical models to do this. Research in animals and humans has started the process of identifying genes affecting the traits associated with healthy ageing such as obesity or bone strength. However it has become clear that traits associated with healthy ageing are generally controlled by large numbers of genes with small effects. To unequivocally find such genes and accurately estimate their effects requires very large studies and relatively few genes have as yet been identified. Thus the amount of variation explained jointly by all the genes found in studies so far is usually much less than 10%, even though genetic variation in total may explain as much as 80% of the overall variation. Alongside genetic information, factors such as age, gender, diet and other lifestyle characteristics are often major contributors to how individuals develop. In addition, it is often known that metabolic or predisposing traits like glucose or lipid concentration in blood may correlate with health. Such traits may be more amenable to measurement or may be measured earlier than overall health status and may be used as indicators or predictors of future health. Thus information can also be combined across traits to improve the accuracy of prediction, and to allow prediction of (unmeasured) correlated traits. With this background we propose to develop mathematical methods which make best use of available genomic information and to combine this information with environmental data and across multiple traits. We will use several different approaches and compare them in their ability to accurately predict performance and how they may be extended to account for data from many traits and environments. We plan to apply and extend methods currently used in animal breeding for the related task of identifying genetically superior animals for breeding. These will be compared with machine learning methods from computer science. We plan to demonstrate the effectiveness of these methods applied to the analysis of data from human populations on body mass index - a proxy for obesity - and blood glucose levels, and will also include in the analyses environmental variables like smoking, diet and exercise. The data are currently available from human studies and methods and results will be relevant to this species. In due course, the methods developed will be directly applicable to companion animals as data become available.

Aberrant organ development leads to human congenital abnormalities. We are investigating the processes of normal organ development and attempting to uncover the events that go wrong resulting in birth defects. One field of interest is the development of the limbs. Each year a large number of infants are born with defects of the arms and/or legs and we are studying a subset which manifest extra fingers and toes. We have identified the genetic mutations that constitute the molecular basis for the defect and propose to investigate how these mutations give rise to hands and feet abnormalities. A second interest is in the region of the viscera that includes the stomach, pancreas, spleen and small intestine. These organs are under strict left/right instructions to grow to one side of the body cavity. When the process of left/right patterning is disrupted a number of abnormalities occur including cardiac and gastrointestinal defects and often congenital loss of the spleen. We propose to study the processes that control the genesis and the placement of these organs.

Melanoma is the most deadly form of skin cancer, and incidence continues to rise rapidly each year. In the UK, 2000 people die prematurely each year from melanoma, and once melanoma has spread there are no current treatments that successfully can be used to treat the disease. One of the ways in which melanoma can develop is from moles and we have developed a mole-to-melanoma model of cancer progression based on the most frequently mutated human gene in melanoma using the vertebrate animal called zebrafish. The way cancer develops and looks in zebrafish is highly similar to human cancers, and the genetic pathways that are altered in zebrafish cancers are the same as in people. The advantage for us with this system is that we can quickly and easily explore the function of many genes in melanoma development, as well as environmental factors that may contribute to disease. We can also test thousands of new and known chemicals in the zebrafish system that may be relevant to melanoma growth and movement in the body. Finally, the same genes that promote melanoma can also cause a syndrome called cardio-facial-cutaneous (CFC) syndrome, and we are developing new ways to look how the knowledge we gain from our melanoma studies may in fact be directly relevant to how we approach treatment for CFC.