Advances in biotechnology, biology and biomedicine, and their impact on the quality of life, the economy, medicine and health care increasingly depend on the application of structural biology which provides detailed structural information of the proteins which are central to all life processes. An important aspect of health and well being in all forms of life is the ability to resist and fight infection and disease, and the molecules which make up the immune response are a very important factor in both resistance and recovery. The immune response has two major methods of defence, the innate immune response, which has been preserved and refined throughout evolution, and the antibody-based response, a relatively recent addition. The innate immune response has non-variable components, including molecules known as collectins, and others called pentraxins, which respond in a fairly general, often rapid manner to threatening microorganisms and molecules of both internal and external origin. The Complement cascade provides one route through which molecules of both innate and adaptive immunity can clear their targets. The collectins in the lung are important in resistance to respiratory disease, allergy and asthma. Those in the blood stream, along with the pentraxins and Complement, enable the destruction of molecules and microorganisms of various kinds. Recent work suggests that the pentraxin human CRP, alongside Complement component C1q, may exacerbate rather than reduce inflammation and these molecules have become targets for inactivation by designed drugs. For the collectins, biotechnology can generate parts of the molecules, including the parts that are involved in binding their targets, and these fragments often retain their defensive properties. A major focus of this research is the definition of the three-dimensional structure of pentraxins and of active fragments of collectins, both in their own right and bound to those parts of their targets which they recognise in real life. This will provide invaluable information for the further design of potential diagnostic and therapeutic agents and strategies, for a variety of diseases, by our collaborators and other investigators.

Rheumatoid arthritis in a common, debilitating and painful disease affecting about 1% of the population and can result in increased mortality. Migration of leukocytes (white cells) from the blood into rheumatoid joints is enhanced by molecules called chemokines. Carbohydrates on the endothelial cells that line blood vessels bind chemokines and present chemokines to leukocytes in the blood. We have found that a particular carbohydrate-bearing molecule, syndecan-3, on the endothelial cells in rheumatoid arthritis binds the chemokine CXCL8. The project aim is to elucidate the importance of syndecan-3-chemokine interactions in rheumatoid arthritis. This will be carried out by studying mice that do not possess syndecan-3. The migration of leukocytes into tissues will be studied in syndecan-3 deleted mice to examine if this differs compared to normal animals. In addition, it will be determined if the severity of arthritis in these mice is altered compared to normal. Therefore this work could lead to greater understanding of disease mechanisms in rheumatoid arthritis and targeting syndecan-3 could ultimately be used as a new type of treatment. The research work will be presented at our annual hospital open day. This day is advertised widely and the general public and scientific professionals visit the laboratories and hear about the medical research being carried out in the hospital and medical school. In addition, we have groups of school pupils come and view the work we perform in order to foster an interest in science. When grants are awarded to our research centre an article is written for the local newspaper (The Shropshire Star) describing the research in lay terms. Furthermore, at a later date the results of the research would be published in popular journals and local or national newspapers as appropriate. All these lay communication activities are part of an existing programme and will not incur extra costs. The work would also be presented to the scientific community and health professionals at congresses in terms of oral and poster presentations, and in written form in published peer-reviewed journals.

Malaria remains a major cause of mortality in many parts of Africa. The control of mosquito populations remains one of the most efficient ways of decreasing the incidence of the disease. This is commonly done by using insecticide-impregnated bednets or by spraying houses. In many areas of Africa however, mosquito populations are becoming resistant to commonly used pesticides. There is thus an urgent need for exploring and developing novel approaches to control or eradicate mosquito populations. Here, two medical entomologists from Burkina Faso and the UK join their expertise to propose an extensive research program focusing on the male reproductive behaviour of Anopheles gambiae, the main vector of malaria in Africa. Male mating behaviour is a key aspect of the mosquito life-cycle and an aspect of their biology that is crucial for the development of several promising vector control strategies. Anopheles gambiae mates in flying aggregations or swarms in which they choose their mate and copulate. Swarms would constitute an ideal target for mosquito population control but very little is known about the cues that male mosquitoes use to locate and initiate their swarms. Here, the researchers propose to build on recent findings from months of observation of swarm formation in their natural habitats to explore the feasibility of predicting and manipulating swarm location for mass killing. Male mating behaviour is also crucial for vector control programs aiming to release sterile male mosquitoes that mate with wild females and induce their sterility and for programs aiming to introduce genes of refractoriness to malaria into mosquito populations via genetically-modified mosquitoes. So far laboratory-reared male mosquitoes have been unable to mate with wild females effectively thereby casting doubt on the efficiency of mosquito releases. An important part of the research program will thus focus on understanding what determines male mating success in swarms with the goal of improving the mating performance of laboratory-reared male mosquitoes. The proposed research studies will include ecological experiments in specially designed large outdoor cages and selected villages in Burkina Faso and will also benefit from the latest molecular advances in the laboratories of the UK partner institution. The novel approaches are expected to strongly impact this field of research and soon benefit communities from countries endemic for malaria by enabling new mosquito control strategies.