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.

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.

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.

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.

Research on particle shape is extremely important to many industrial applications such as pharmaceuticals, biopharmaceuticals, human health products and speciality chemicals. For example, for pharmaceuticals, the morphology can affect important properties such as dry powder density, cohesion, and flowability, that can have major impact on a company's ability to formulate drug particles into finished products. Moreover, crystal morphology can affect drug dissolution, potentially affecting formulated product bioavailability and, in extreme, resulting in a companies loss of the license to making the drug product. However, despite the availability of various Process Analytical Technology (PAT) instruments for measuring other properties of particulate systems, there have been no effective on-line instruments capable of providing real-time information on particle shape during the processing of particles in unit operations such as crystallisation, precipitation, granulation and milling. In the past few years, on-line high speed imaging has shown to be a very promising PAT instrument for real-time measurement of particle shape on-line which has resulted in the development of some new instrumentation products just released to the market such as the PVM (Process Vision system) of Lasentec (uk.mt.com), the PIA (Process Image Analyser) of MessTechnik Schwartz GmbH (www.mts-duesseldorf.de), the ISPV (In-Situ Particle Viewer) of Perdix (www.perdix.nl) in Netherlands, and the On-line Microscopy systems of GlaxoSmithKline, some of which incorporate a probe design which allows easy access to a processing reactor vessel. However, all these techniques are essentially limited in that they can only provide 2D information of the particle shape. Hence, this proposed research aims to develop a new instrument Stereo Vision Probe which can directly image the full 3D shape of particles within a practical processing reactor. This basic mode of operation is based on the mathematical principle that if the 2D images of an object are obtained from two different angles, the full 3D particle shape can be recovered. The potential impact on research capability and industrial applications is predicted to be major but the proposed research will focus on the development of the Stereo Vision Probe and the 3D construction method from the two 2D images obtained from two different angles. The testing of the system will be mainly via the use of a variable temperature crystallisation cell.