It is very difficult to study the function(s) of specific groups of neurons because the brain contains thousands of different cell types that are juxtaposed and interconnected and vary according to their size, shape, projections and function. Recently a method has been developed that allows all the molecules (messenger RNA) that are being translated into proteins to be in defined in specific neuronal populations. This is a very powerful tool as for the first time the sets of genes that are governing neuronal function (e.g. those controlling the formation of memories) and those that are altered with age and in human neurodegenerative and neuropsychiatric illnesses can be identified. However, this method is dependent on costly transgenic mice lines, and each time a new scientific question is asked a new mouse line needs to be generated. The technique itself is quite complex, and time consuming due to the need to develop and breed (and in many cases cross breed) one or more mouse lines. These considerations severely limit the availability of this technique to researchers and instead a combination of less powerful approaches must be used. In this study we are combining the expertise of Takeda and the University of Bristol to develop two new methods. These methods use viral vectors instead of transgenic mice (called viral TRAP) and allow neurons to be profiled with a speed, precision and versatility not previously possible with transgenic mice alone. These viral TRAP methods will also result in fewer animals being used by researchers. The viral TRAP technique will be used by the University of Bristol to identify the genes and proteins a family of RNA binding proteins called scaffold attachment factors (SAF) regulate. In particular this information will be used to understand how SAF proteins govern the processes that regulate memory formation and ageing. The viral TRAP technology will enable Takeda to perform detailed profiling experiments without the need for lengthy, expensive and animal-intensive transgenic programs. Importantly as the viral TRAP technique is portable to other models that Takeda currently use the technology will provide a novel platform that will greatly facilitate both basic biology and future pharmacological response studies. Ultimately, the objective of Takeda is to use this technology to further the understanding of neuronal gene regulation and homeostasis in response to challenge, and to use these insights to identify novel targets for central nervous system disorders.

Together with industrial partners, we have established that there is a strong unmet demand for individuals with expertise in the combination of statistics, applied mathematics, computation, and the collaborative problem solving skills required to acquire application area knowledge. Consider, for example, aircraft structural design, where statistical methods have recently been approved in the certification of aircraft, complementing traditional experimental testing. This ushers in a change in possible design methodology, but creates a corresponding gap for the necessary talent in the workforce: scientists with knowledge of materials, computational methods and statistics. Such individuals are needed to sustain the UK's global competitive advantage, industrially and academically. We propose a world leading and innovative cohort-driven centre for doctoral training at the interface of Statistics and Applied Mathematics: Statistical Applied Mathematics at Bath (SAMBa). Modern mathematical models describing real world applications must incorporate randomness and data in a variety of ways in order to improve their ability to predict complex behaviour and describe empirical observations. Traditionally, deterministic applied mathematics and statistical methods have taken different approaches in modelling observed phenomena. More recently, we have seen that this is proving to be a hindrance to the competitiveness of British mathematics, especially when taking account of the enormous scope for research with genuine real-world impact. SAMBa will create a new generation of interdisciplinary mathematicians, both for academic careers as well as for insertion into British industry. Their primary strengths will be their problem solving ability and their fearlessness of barriers separating mathematical modelling and modern statistics. Moreover, the implementation of this CDT will promote a novel way of educating UK PhD students within the mathematical sciences, in which there is horizontal cross-disciplinary and industrial integration through CDT activities. The central mechanism by which this horizontal integration will occur will be through week-long Integrative Think Tanks (ITT), which share similarities with sandpits. These ITTs will be supported by an array of new courses that span a spectrum including statistics, stochastic simulation and applied mathematics. SAMBa will enrol ten students per year on a four-year study programme. The first year will focus on the new courses and in the formation of research themes, as well as developing cohort integration. ITTs will occur at the end of the first and second semesters during the first year of study, and will give students the opportunity to learn how to formulate problems and structure their approach to problem solving. ITTs will be intensive activities, managed by academic staff together with interdisciplinary and industrial leaders. Students in later years will participate in one ITT per year with a view to enhancing the PhD cohort experience. The expected outcomes of the ITTs will be: to provide real experiences in approaches to problem solving, to promote cross-fertilisation of ideas and expertise through horizontal integration, to build a cohesive PhD student cohort, to catalyse new collaborations, and to provide a source of PhD thesis projects. It is expected that most, but not all, PhD thesis problems and supervisory teams will emerge from ITTs. PhD students will also run a symposium series to prepare for, and subsequently reinforce, the ITT experience as well as to develop the students' sense of research empowerment. Students in SAMBa will be awarded an M.Res. after one year, subject to successful assessment. In addition, we will strongly encourage three month industrial or cross-disciplinary academic placements. These placements will enhance the horizontal integration and are a natural extension of our long-standing and thriving BSc an MSc placement scheme.

Regenerative medicine (RM) is a convergence of conventional pharmaceutical sciences, medical devices and surgical intervention employing novel cell and biomaterial based therapies. RM products replace or regenerate damaged or defective tissues such as skin, bone, and even more complex organs, to restore or establish normal function. They can also be used to improve drug testing and disease modelling. RM is an emerging industry with a unique opportunity to contribute to the health and wealth of the UK. It is a high value science-based manufacturing industry whose products will reduce the economic and social impact of an aging population and increasing chronic disease.The clinical and product opportunities for RM have become clear and a broad portfolio of products have now entered the translational pipeline from the science bench to commercialisation and clinical application. The primary current focus for firms introducing these products is first in man studies; however, success at this stage is followed by a requirement for a rapid expansion of delivery capability - the 'one-to-many' translation process. This demands increasing attention to regulatory pathways, product reimbursement and refinement of the business model, a point emphasised by recent regulatory decisions demanding more clarity in the criteria that define product performance, and regulator initiatives to improve control of manufacturing quality. The IMRC will reduce the attrition of businesses at this critical point in product development through an industry facing portfolio of business driven research activities focussed on these translational challenges. The IMRC will consist of a platform activity and two related research themes. The platform activity will incorporate studies designed to influence public policy, regulation and the value system; to explore highly speculative and high value ideas (particularly clinically driven studies); and manufacturing-led feasibility and pilot studies using state of the art production platforms and control. The research themes will focus on areas identified as particular bottlenecks in RM product translation. The first theme will explore the delivery, manufacturing and supply processes i.e. the end to end production of an RM product. Specifically this theme will explore using novel pharmaceutical technology to control the packaged environment of a living RM product during shipping, and the design of a modular solution for manufacturing different cell based therapies to the required quality in a clinical setting. The second research theme will apply quality by design methods to characterise the quality of highly complex RM products incorporating cells and carrier materials. In particular it will consider optical methods for non-invasive process and product quality control and physicochemical methods for process monitoring.The IMRC will be proactively managed under the direction of a Board and Liaison Group consisting of leading industrialists to ensure that the Centre delivers maximum value to the requirements of the business model and assisting the growth of this emerging industry.

A substantial part of animal, including human behaviour is goal-directed. Learning how to achieve a defined goal requires the interplay between higher brain centres involved in planning and decision making, and subcortical structures that co-ordinate the desired movement. The prefrontal areas of the cerebral cortex are thought to be especially concerned with the planning and decision making aspects of such tasks, while the cerebellum is heavily involved in co-ordinating the desired action. However, recent studies in humans and patients are challenging this division of labour and it is increasingly being recognised that the contribution of the cerebellum goes beyond movement control to include many other aspects of brain function, including a contribution to cognitive processes. The cerebellum is linked to structures throughout the central nervous system, from the spinal cord to prefrontal cortex. An important organizational principle of the cerebellum for understanding these widespread connections is a division into a series of anatomical/functional units called modules. How individual modules contribute to goal-directed behaviour remains far from clear. Individual cerebellar modules are thought to contain representations (internal models) of predictable behaviour that allow us, through practice, to execute tasks more rapidly and with increased accuracy. The current project uses the modular organization of the cerebellum combined with the computational capability of internal models as a structural and theoretical framework to study prefrontal-cerebellar network interactions during goal-directed behaviour. An important gap in our understanding of prefrontal-cerebellar interactions is investigation in animal models of large scale brain networks in terms of information processing at the level of recording neural population activity and spike trains of individual neurones; and also interventionist work to dissect out the functional importance of the interactions. Linking the study of higher centres to movement control also has the advantage that 'cognition' is constrained in the sense that it is being studied in relation to well defined behavioural outputs. In collaboration with our industrial partner (Takeda Cambridge Ltd) we will therefore use the combined power of multichannel electrophysiological recording, stimulation, functional anatomical and behavioural techniques at the systems level of analysis to advance our understanding of the function of brain circuits involved in goal-directed behaviour. Choice of experimental model: cerebellar network architecture and patterns of connectivity are highly conserved across mammalian species, including human. However, adult rats are the experimental animal of choice because our understanding of the basic neuroanatomy and physiology is most complete in this species. Importantly, our experiments will include study of neural network interactions during behavioural situations that have been well characterized in rats and that correlate to human cognitive performance. We will study neural network dynamics in prefrontal-cerebellar circuits during cognitive task performance before and after transcranial stimulation of the cerebellum. The latter has been shown in human studies to improve cognitive task performance but the underlying neurobiology is unknown. In complementary functional anatomical studies our industry partner will chart the pattern of neural network activation produced by transcranial cerebellar stimulation. The results of our project aim to provide fundamental new insights into how neural circuits within the brain give rise to our ability to modify our actions to achieve a particular goal.

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.