Parasitic worms (nematodes) represent one of the most serious health problems of grazing livestock (sheep, cattle and goats) in the UK and throughout the world, causing significant economic loss and animal welfare problems. The most important types of parasitic worms live in the stomach and intestine of their animal host. Some cause diarrhoea, which can be severe, whilst others feed on blood and cause internal bleeding and anaemia. Severely affected animals may die, or have to be destroyed on welfare grounds, whilst more mildly affected animals have sub-optimal growth rates which can have serious economic implications for the farmer. Indeed, parasitic worms the most economically important disease of sheep and have been estimated to cost the sheep industry in the region of £80M per annum. They are similarly important in cattle. These economic losses are directly related to the severity of infection and so by reducing the number of parasites infecting livestock, we can proportionally reduce the costs to the industry as well as improving animal welfare. Control of these parasites is heavily dependent upon the routine treatment of livestock with drugs (anthelmintics, commonly called wormers) and there are only three major types available. In many parts of the world, parasitic worms are now resistant to all of these drugs. In the UK, over 60% of sheep worms are resistant to at least one drug class and multiple resistance is increasing. Consequently, the problem of drug resistant worms is a significant threat to the sustainability of the UK sheep and cattle industries. Detection of resistance is problematic and current methods are old fashioned, labour-intensive and very insensitive, making diagnosis unreliable and early detection impossible. Consequently, there is a need to develop modern sensitive tests for routine diagnosis and surveillance and as tools to study the way in which drug resistant parasites appear and spread. An understanding of these issues is critical for the design of parasite control regimes that are both effective and sustainable and to develop ways of using these important drugs that do not exacerbate the development of resistance This project aims to develop and apply tools to elucidate a number of key aspects of the biology and genetics of these parasites that will help us understand how drug resistance develops and how it may be combated. Sheep worms will be studied because drug resistance is the most advanced in these parasites and they are amenable to experimental work. The project will also develop a genome sequence database that will not only enable us to study the problem of resistance but will assist other researchers to develop vaccines and identify new drug targets in these parasites. The research team will be multidisciplinary and include vets and scientists with expertise in genetics, molecular biology, genomics, epidemiology, statistics, parasitology and clinical veterinary medicine. The first stage of the project will be to establish the tools needed, including DNA sequence and genetic markers from the two major parasite species of parasite to be studied. In parallel to this work, parasite samples will be collected from sheep throughout the UK and molecular-based diagnostic tests used to determine the species present. The genetic markers that have been developed will then be used to 'fingerprint' the parasite populations to investigate their genetic diversity. Parasite genes that are already known to confer resistance will be sequenced to investigate the different ways parasites are becoming resistant to these drugs and to provide information that will pave the way for the development sensitive diagnostic tests based on parasite DNA typing. Finally, a system of genetic analysis, not previously applied to parasitic worms, will be investigated that will scan the worm's genome to identify regions containing previously unknown resistance-conferring genes.

Thickening of blood vessels (known as remodelling) occurs in many diseases associated with the cardiovascular system and is related to high blood pressure (hypertension). This can occur in the blood vessels that supply the lungs (pulmonary arteries), those that supply the heart and the brain as well as those that supply blood to the rest of the body (systemic arteries). Many factors contribute to the remodelling of arteries. Recent evidence suggests that a chemical in the body known as serotonin can interact with another chemical known as mts1 to cause pulmonary arterial remodelling. This has been shown in isolated cells but whether or not this occurs in the whole animal requires investigation. We have established techniques designed to investigate pulmonary and systemic arteries in transgenic mice, both in the whole animal, at the level of the very small arteries and at the cellular level. Application of these techniques to mice that have an artificial increase in the expression of the pore that allows serotonin to enter the cell (the serotonin transporter) and mts1 will enable us to investigate this potentially important mechanism for vascular remodelling. In addition, lack of oxygen (hypoxia) is an important mediator of pulmonary arterial remodelling and we have developed techniques for exposing mice and cells to a hypoxic environment. This will be applied to study the interaction between hypoxia, serotonin and mts1. The major aim of the work is to establish, in the whole animal, if there is an important interaction between mts1 and serotonin that causes a remodelling of the pulmonary arteries. This will be done by examining these interactions in mice over-expressing mts1 and mice over-expressing the serotonin transporter. These mice will also be cross-bred to develop mice that over-express both the serotonin transporter and mts1. Further experiments will be carried out on blood vessels derived from these 'models' and from cells grown up in culture from these blood vessels. This will give a clear picture of how intracellular interactions relate to whole body function. There are many benefits and applications of this work, including knowledge of how mts1, serotonin and hypoxia affect vascular function, how this changes in disease and how such changes could be prevented. It will suggest novel therapies for remodelling diseases such as hypertension.

These studies will help design new vaccines for two important diseases of cattle, bovine tuberculosis and Foot-and-Mouth disease virus. Mycobacterium bovis is the causative agent of bovine tuberculosis (TB), a disease increasing in incidence in UK cattle herds causing major economic losses and potential human health risks. At present control of bovine TB relies solely on the use of diagnostic tests which do not have 100% sensitivity or specificity. Foot and mouth disease virus (FMDV) has a wide host range including all cloven-hoofed animals and causes an acute vesicular disease in domestic ruminants and pigs, which results in debilitation, pain and loss of productivity. Vaccines have been shown to be highly valuable in controlling a variety of infectious diseases, including bacteria and viruses. However, effective vaccines require portions of the infectious agent to be delivered to specialised cells, called dendritic cells. Dendritic cells are the only cells in the body capable of starting an immune response to an agent the body hasn't seen before. Targeting portions of the infectious agents to dendritic cells has been shown to stimulate a strong immune response. Unfortunately, the situation is more complicated than it first appears, there is more than one type of dendritic cell and each cell type can stimulate a different type of immune response. Specific immune responses may be required to control different infections. Acute viral infections, for example Foot-and-Mouth disease, may require an antibody response to control infection. In contrast, slow growing bacterial infections, for example tuberculosis may require immune T cells to control them. In this programme of work we plan to target components of Foot-and-Mouth disease virus or cattle tuberculosis bacteria to particular dendritic cell subsets to determine whther a protective immune response can be stimulated

The biggest health issue facing the UK is the increasing prevalence of obesity (excess storage of fat). We live in a society where energy-rich food is generally cheap and easily available, and where we have very sedentary life styles. Therefore, our natural ability to regulate our body weight is being undermined. Obese and even moderately-overweight individuals have greatly increased chances of developing diabetes, vascular diseases and cancer: making the treatment of obesity-related diseases an enormous burden on the National Health Service and similar agencies around the world. Many organs, including fat tissue, the liver and the pancreas, interact to regulate both our body weight and the availability of the fuels that we need for our bodies to function normally. However, it is the brain that co-ordinates this regulation. Thus, we need to understand how the brain detects and responds to all the different sources of information that ultimately determine how much we eat and how much body fat that we store. It is not surprising that, due to the complexity of the brain, we still have only a limited understanding of how this organ carries out the function. The brain has complex circuits that act to try and balance our food intake to our energy needs. Unfortunately, in humans appetite is controlled less by physiological requirements and more by other factors such as what time of the day it is, if we like or dislike the food that is available or if we are eating with other people. One of the biggest problems with controlling our eating is that it is a pleasurable and sociable experience. Thus, we tend to choose sweet or fatty foods / the worst kind if we wish to reduce our weight / and we tend to eat even if when we are replete. We will develop cutting-edge technology to image the brain's response to a number of different stimuli that affect appetite. Thus, using a powerful magnetic resonance imaging (MRI) machine, similar to that used in everyday clinical diagnosis, we will determine which part of a rat's brain is important for detecting and responding to these signals. We will test a number of stimuli that increase appetite in order to assess how different parts of the brain interact. As the rat is anaesthetised throughout the imaging, the stimuli will artificially mimic the feelings of hunger and the pleasure of eating. We will use this information to understand normal brain functioning, how this may differ with the development of obesity and how treatments may be able to help. This knowledge will benefit academics, health professionals and the pharmaceutical industry, enabling them to improve care and to develop drugs for problems as diverse as obesity and anorexia.

THE CENTRE: The Manchester Centre for Integrative Systems Biology (MCISB) has been founded recently, as one of three Systems Biology centres of excellence granted by the BBSRC and EPSRC. Operating from a rich science & technology base in the disciplines around and in Systems Biology (SB) ranging from e-science GRID computing to molecular biology, it has already attracted industrial support and Systems Biologists from elsewhere, such as Westerhoff (accepting the AstraZeneca Chair of Systems Biology), Snoep (Silicon cell), Tsujii (Tokyo GENIA/bio-text mining), adding to SBists such as Oliver, Kell and others. The pending appointment of an EPSRC Chair in Computational Systems Biology and approximately 10 more appointments ranging from professor to lecturer will consolidate the MCISB as a world leading institute in Systems Biology. We here propose to make this MCISB the home of an EPSRC/BBSRC Doctoral Training Centre for Systems Biology.