Our ability to sense changes in pressure and temperature, as well as our ability to detect a wide variety of chemical agents, is not only essential for normal bodily function, but also for the perception of pain. Understanding the molecular mechanisms which control these processes represents one of the most important goals in sensory biology. When our body comes into contact with potentially dangerous stimuli a complex series of events initiates innate protective mechanisms designed to minimize or avoid injury. For example, extreme temperatures, mechanical stress, and chemical irritants such as acid are detected by specialised receptors clustered at the ends of sensory nerve fibres which convert these stimuli into electrical signals. These signals are then rapidly transmitted from distant sites in the body to the spinal cord and to higher processing centres in the brain which interpret these signals to initiate an appropriate response. These electrical signals are orchestrated by distinct groups of cell membrane proteins known as 'ion channels' of which there are many hundreds of different kinds in the human body. However, there is now significant evidence that one particular group known as the 'two-pore' or 'K2P' family of potassium selective channels play an important role at many different stages of this pathway, including the specific detection of both normal and painful stimuli. Although the sensation of pain is generally beneficial for the avoidance of greater overall tissue damage, unwanted pain confers a substantial burden on individuals, employers, healthcare systems and society in general. Indeed, the personal and socioeconomic impact of chronic pain is as great as, or greater, than that of other established healthcare priorities. There is therefore a tremendous need for better and more effective drugs for the treatment of pain and K2P channels represent attractive therapeutic targets for such drugs. In a major recent advance, we have now determined the 3D structures of two human K2P channels (TREK-1 and TREK-2) using X-ray crystallography. We were also able to determine their structures in different conformational states which has provided new insights into how these channels open and close to 'switch' electrical signals on and off. More importantly, we were also able to solve the structure of TREK-2 in complex with an inhibitor, fluoxetine (Prozac). Although not the principal target of this drug, identification of the binding site has provided an important insight into the biophysical mechanisms of TREK-2 channel gating and regulation by small molecules, as well as some of the potential off-target effects of this commonly prescribed drug. In this research project we aim to exploit these exciting new findings to define a structural basis for how K2P channels open and close to control electrical signals, and also to understand how other small molecules and physiologically relevant regulatory pathways control this process. The proposed industrial partnership with Pfizer Neusentis also provides us with access to a variety of chemical tools, expertise and resources not normally available in a standard academic environment, and therefore places us in a unique position to be able to pursue these goals.

We will improve patient health and medical research by maximising the use of vast amounts of human data being generated in the NHS. But there are two obstacles: (i) inter-related clinical and research datasets are dispersed across numerous computer systems making them hard to integrate; (ii) there is a serious shortage of computational expertise as applied to clinical research. As part of the UK's healthcare strategy to overcome these limitations, we have assembled a world-class consortium of institutions and scientists, including UCL Partners (containing NHS Trusts treating >6 million patients), Francis Crick Institute, Sanger Institute and European Bioinformatics Institute. Close links with the NHS (through Farr and Genomics England) will allow information exchange for health and disease progression. We have also engaged leading companies like GSK and Intel. We will use the MRC funds for two purposes: 1. Create a powerful eMedLab data centre. We will build a computer cluster that allows us to store, integrate and analyse genetic, patient and electronic health records. By co-locating in a single centre, we eliminate delays and security risks that occur when information is transmitted. Research Technologists supplied by the partners will install and maintain the infrastructure and software environment. 2. Expand scientific and technical expertise in UK Medical Bioinformatics through a Research & Training Academy. Basic and clinical scientists, and bioinformaticians will be trained to perform world-leading computational biomedical science. We will train in the whole range of skills involved in medical bioinformatics research with taught courses, seminars, workshops and informal discussion. To coordinate research activities across partners, we will establish Academy Labs, which are flexible, semi-overlapping groupings of academic and industrial researchers to share insights and plan activities in areas of common analytical challenges. The Academy will provide a mechanism for information and skills exchange across the traditional boundaries of disease types. These will enable existing projects in 3 disease domains in which we have unique strengths: rare diseases, cardiovascular diseases and cancer. Rare: We house 31/70 Nationally Commissioned Highly Specialised Services; ~0.5M of the 6M of our patients have a rare disease, including >50% of those treated at Great Ormond Street Hospital. >200 research teams generate large quantities of genetic, imaging (eg, 3D facial reconstructions), and clinical information (eg, patient records). Cardiovascular: We also lead genomic, imaging, and health informatics programmes in cardiovascular disease with contributions to projects like UK10k project and host multiple national cardiovascular registries through the National Institute for Cardiovascular Outcomes Research. These are linked to primary and hospital clinical care records through Farr@UCLP with current cohort sizes of ~2M people. Cancer: We also have particular clinical expertise in some of the most difficult to treat cancer types and we host major international data resources. These include individuals recruited to the TRACERx study of lung cancer, 8,500 women with abnormal cervical smears in whom methylation patterns of the HPV16 genome predict progression to high-grade precursor disease, and one of the largest sarcoma biobanks in the world. Ultimately, this bid will allow us to use new computational approaches to (i) link patient records and research data in order to understand the pathogenesis of disease, (ii) use genomic, imaging and clinical data to identify diagnostic, prognostic and predictive biomarkers to guide therapy, predict outcome and increase recruitment to clinical trials based on stratified populations and (iii) translate new IP by engagement with the pharmaceutical industry.

The traditional PhD programme begins with a student seeking out a PhD position early on in their final year of undergraduate study. The time elapsed between a student choosing their project and actually starting is generally between 6-8 months - can a student really be sure that the right choice has been made under these circumstances? This choice is probably the most important decision an aspiring professional researcher can make, yet students can make ill informed, naive or simply unsuitable PhD choices based on their perceived interests and limited research experience. Bristol Chemical Synthesis (BCS) is a Centre for Doctoral Training (CDT) that offers a different and much enhanced PhD training experience to the traditional path. Crucially, students join the Centre in October but do not choose their PhD research project until 7-months later. Students spend these 7-months completing a unique, multifaceted training period called Postgraduate Advanced Chemical Techniques (PACT). The over-arching goal of PACT is to equip the students with the tools required to make the best-informed PhD project choice, to develop a creative attitude towards problem solving and to build self-confidence with presentations and by speaking publicly. PACT also provides a formal assessment mechanism before students progress to their PhD projects. Brainstorming involves the students generating ideas on outline research proposals which they then present to the staff members in a lively and engaging feedback session, which invariably sees new and student-driven ideas emerge. By encouraging teamwork and presentation skills, as well as allowing students to become fully engaged with the projects and staff, brainstorming ensures that students take control of a PhD proposal before they start - 'Partners not Slaves' is our vision. Research Broadening Sabbaticals comprise three successive 7-week lab rotations designed to include a period of "known" work, enabling the student to practice new skills required for further research. Rotations are important in giving students the opportunity to learn new techniques beyond their undergraduate experience, providing them with time to consider and reflect on their choice of PhD by offering "tasters" in different areas of synthetic chemistry. Dynamic Laboratory Manual (DLM) enabled experiments allow students to experience an interactive, virtual version of an essential experimental technique. Pioneered at the undergraduate level at Bristol, DLMs consist of a mixture of simulations, videos, tutorials and quizzes to allow the student to gain a full understanding of a technique and learn from mistakes quickly, effectively and safely before entering the lab. Chemical Synthesis is an area upon which much of modern society relies as it enables the customised fabrication of products that are the essential materials of our daily lives. Examples are wide and diverse from vital life saving drugs to the chromic materials that make your iPad screen change in an instant. There are 15 key UK industry sectors in which chemistry is an essential component, employing over 5 million people and contributing £258bn (21%) to the UK's GDP. Pharma, agrochem, petrochem, fine & bulk chemical manufacturing and CRO industries are major players in these industries and UK competitiveness here is unsustainable without the continued supply of highly trained & skilled chemical synthesis PhD graduates. Our Centre will train the next generation of synthetic chemistry architects equipped to solve the diverse molecular problems of the future.

Modern society is reliant on chemical synthesis for the discovery, development and generation of a wide range of essential products. These include advanced materials and polymers, bulk fine chemicals and fertilizers, and most importantly products that impact on human health and food security such as medicines, drugs, and agrochemicals. Future developments in these areas are benficial for society as a whole and also for a wide range of UK industries. To date it has been common practice for the chemical industry to recruit synthetic chemists after PhD/postdoctoral training and then augment their synthetic knowledge with specific industrial training. Due to the changing nature of the chemical and pharmaceutical industry it is recognized that synthetic chemists require an early understanding of the major challenges and methodologies of biology and medicine. The concept of our SBM CDT arose from the need to address this skills gap without compromising training in chemical synthesis. We have designed a training programme focused on EPSRC priorities to produce internationally outstanding doctoral scientists fluent in cutting edge synthesis, and its application to problems in biology and medicine. To achieve this, we have formed a genuinely integrated public-private partnership for doctoral training whereby we combine the knowledge and expertise of industrialists into our programme for both training and research. We have forged partnerships with 11 global industrial partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) and a government agency (DSTL), which have offered: (i) financial support (£4.6M cash and £2.4M in-kind); (ii) contributions to taught courses; (iii) research placements; and (iv) management assistance. Our training partners are global leaders in the pharmaceutical and agrochemical industries and are committed to the discovery, development and manufacture of medicines and agrochemicals for the improvement of human health. To fully exploit the opportunities offered by commercial partners, the SBM Centre will adopt an IP-free model to allow completely unfettered exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies; this would not be possible under existing studentship arrangements. This free exchange of research data and ideas will generate highly trained and well-balanced researchers capable of world-leading research output, and importantly will enable students to benefit from networks between academic and industrial scientists. This will also facilitate interactions between different industrial and government groups, leading to links between pharmaceutical and agrochemical scientists (for example). The one supervisor - one student model, typical of current studentship programmes, is unable to address significant and long-term training and research topics that require a critical mass of multidisciplinary researchers; consequently we propose that substantive research projects will also be cohort-driven. We envisage that this CDT will have a number of training and research foci ('Project Fields') in which synthesis is the unifying core discipline, to enable our public-private partnership to tackle major problems at the chemistry-biology-medicine interface. Our focused research fields are: New Synthetic Methods, 3D Templates for "Lead-Like" Compounds, Functional Probes for Epigenetics, Next Generation Anti-Infectives, Natural Product Chemistry and Tools for Neuroscience. This doctoral training programme will employ a uniquely integrated academic-industrial training model, producing graduates capable of addressing major challenges in the pharmaceutical/agrochemical industries who will ultimately make a major impact on UK science.