The CDT in Molecules to Product addresses an overarching concern articulated by industry operating in the area of complex chemical products. It centres on the lack of a pipeline of doctoral graduates who understand the cross-scale issues that need to be addressed within the chemicals continuum. Translating their concern into a vision, the focus of the CDT is to train a new generation of research leaders with the skills and expertise to navigate the journey from a selected molecule or molecular system through to the final product that delivers the desired structure and required performance. To address this vision, three inter-related Themes form the foundation of the CDT - Product Functionalisation and Performance, Product Characterisation, and Process Modelling between Scales. More specifically, industry has identified a real need to recruit PGR graduates with the interdisciplinary skills covered by the CDT research and training programme. As future leaders they will be instrumental in delivering enhanced process and product understanding, and hence the manufacture of a desired end effect such as taste, dissolution or stability. For example, if industry is better informed regarding the effect of the manufacturing process on existing products, can the process be made more efficient and cost effective through identifying what changes can be made to the current process? Alternatively, if there is an enhanced understanding of the effect of raw materials, could stages in the process be removed, i.e. are some stages simply historical and not needed. For radically new products that have been developed, is it possible through characterisation techniques to understand (i) the role/effect of each component/raw material on the final product; and (ii) how the product structure is impacted by the process conditions both chemical and mechanical? Finally, can predictive models be developed to realise effective scale up? Such a focus will assist industry to mitigate against wasted development time and costs allowing them to focus on products and processes where the risk of failure is reduced. Although the ethos of the CDT embraces a wide range of sectors, it will focus primarily on companies within speciality chemicals, home and personal care, fast moving consumer goods, food and beverage, and pharma/biopharma sectors. The focus of the CDT is not singular to technical challenges: a core element will be to incorporate the concept of 'Education for Innovation' as described in The Royal Academy of Engineering Report, 'Educating engineers to drive the innovation economy'. This will be facilitated through the inclusion of innovation and enterprise as key strands within the research training programme. Through the combination of technical, entrepreneurial and business skills, the PGR students will have a unique set of skills that will set them apart from their peers and ultimately become the next generation of leaders in industry/academia. The training and research agendas are dependent on strong engagement with multi-national companies, SMEs, start-ups and stakeholders. Core input includes the offering, and supervision of research projects; hosting of students on site for a minimum period of 3 months; the provision of mentoring to students; engagement with the training through the shaping and delivery of modules and the provision of in-house courses. Additional to this will be, where relevant, access to materials and products that form the basis of projects, the provision of software, access to on-site equipment and the loan of equipment. In summary, the vision underpinning the CDT is too big and complex to be tackled through individual PhD projects - it is only through bringing academia and industry together from across multiple disciplines that a solution will be achievable. The CDT structure is the only route to addressing the overarching vision in a structured manner to realise delivery of the new approach to product development.

Until very recently, pain in people was considered to be a single uniform entity; the nature of the pain experienced by an individual was considered to be similar regardless of the underlying cause. However this concept has now been challenged, which of course fits with everyone's own unique experience of pain resulting from tissue injury, trauma or surgery. The nature and quality of pain caused by each disease condition is different and reflects the underlying changes in the sensory system responsible for causing pain. For example, people may show differing changes in sensitivity to warm or cold stimuli, reflecting different underlying aetiologies or mechanisms of pain. In man this has led to personalized therapy for pain. It is now possible, in people, to identify distinct pain patterns (termed pain phenotype) that relate to distinct changes in sensory processing and target these underling changes in sensory processing with specific drugs. This has resulted in improved pain management in people in chronic pain. The aim of this current proposal is to translate the concept of personalized pain therapy from people to dogs and subsequently increase our capability to provide adequate pain relief to dogs suffering from chronic pain. A very common cause of chronic pain in dogs is osteoarthritis. We currently assume that all dogs with osteoarthritis suffer similarly from pain and show similar altered sensitivity to sensory stimuli such as heat and pressure. However, in people suffering from osteoarthritis, different types of pain associated with different sensory sensitivities are recognized, and these distinct pain patterns are likely associated with different underlying changes in the sensory nervous system. We predict, given the similarity between the disease of osteoarthritis in dogs and man, we will be able to identify similar distinct pain patterns in dogs suffering from osteoarthritis. We will study pet dogs with osteoarthritis, recruited through liaison with veterinary surgeons. The dogs will benefit from a detailed clinical assessment of their osteoarthritis with follow up advice about optimising their pain management, provided by European Specialists in canine osteoarthritis and animal pain management. A major discriminator in the underlying pain mechanisms is whether the pain results primarily from changes in sensory processing in the peripheral nervous system (i.e. in the processing of sensory stimuli localised to the site of the disease process, in the case of osteoarthritis this would be the affected joint) or whether pain is caused by changes in the periphery (the joint) and in the central nervous system (i.e. the spinal cord and brain). Once pain is associated with peripheral AND central nervous system changes it becomes much more difficult to manage effectively and also requires different pain management strategies, for example different types of pain killing drugs are necessary. We will use a simple, validated experimental paradigm to distinguish whether both peripheral OR peripheral AND central changes in sensory processing are present in individual dogs with osteoarthritis. This test will be carried in dogs that are anaesthetised and therefore unaware. Subsequently, in awake animals, we will map the individual pain pattern or pain phenotype to allow us to link pain mechanism with clinical pain expression. This will be achieved by testing sensitivities to warmth, heat, cold and pressure stimuli. Ultimately, we hope that a veterinary surgeon will be able to examine a dog with osteoarthritis in their clinic, and determine using simple and non-invasive tests, their pain phenotype, and use this information to derive knowledge of the underlying pain mechanisms. This will allow the veterinary surgeon to target or personalize pain medication to the patient, with the goal of improved pain management and the lifelong welfare of the individual animal.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Traumatic brain injury (TBI) is commonly associated with falls, road traffic and assaults and has a massive impact upon the community; it is the leading cause of death and disability in the first four decades of life, costing the UK economy an estimated £8 billion per year. Current standard care centers upon neurosurgical intervention and stabilization, yet mortality is relatively high and many that survive suffer life-time disability. Despite the obvious unmet clinical need, there are no approved drugs available in the clinic to reduce the impact of TBI on the patient. Whilst it would be difficult for a drug to reduce the consequences of the initial injury, it is well recognised that the dead and dying brain tissue associated with the initial trauma gives rise to inflammation that spreads to surrounding brain tissue that may be damaged but not irreversibly. However, the added stress of inflammation to this adjacent brain tissue expands the volume of brain damage. This secondary non-mechanical brain damage begins over hours to days after the initial TBI event and is hence considered amenable to potential treatment with drugs. It is well recognized in the scientific literature that a drug target called the P2X7 receptor is involved in the physiological processes that stress brain tissue and can lead to brain cell death - indeed the term 'death receptor' has been coined for the P2X7 receptor. Initial activation of the P2X7 receptor causes excitation of brain cells resulting in their secretion of chemicals that increase inflammation, adding to the stress upon brain cells from the inflammatory environment post-TBI. With more prolonged activation of the P2X7 receptor, the receptor changes shape such that it forms relatively large pores in the cell membrane, which further stresses the cells and can lead to cell death. We believe that blocking the P2X7 receptor with a drug will put a brake on the processes contributing to stressing the brain cells and so help reduce the secondary brain damage subsequent to TBI. We predict this will improve the clinical outcomes for patients following TBI allowing more patients to survive and reduce disability. It is fortunate that, through a collaboration with the pharmaceutical company Pfizer, we will be able to use a drug, code name CE-224,535, that is selective in its ability to block the P2X7 receptor. In addition, clinical studies to date using CE-224,535 in healthy volunteers and patients with arthritis have shown that the drug is well tolerated following oral administration. Our studies will take a step-wise approach. We will first use small pieces of brain tissue from TBI patients undergoing neurosurgery - this brain tissue comes away from the brain during standard neurosurgical techniques and hence its collection does not change the outcome for the patient. Results from experiments with these cells will enable a prediction concerning the concentrations of CE-224,535 that need to get into the brain of patients with TBI to block the P2X7 receptor, which we predict will be beneficial for the patient. We will then perform a clinical trial with CE-224,535 given to TBI patients with the primary purpose of the clinical trial to assess whether CE-224,535 is well tolerated and reaches concentrations in the injured part of the brain that will block the P2X7 receptor. We will also monitor any effect of the drug on biological chemicals that act as markers for cell damage and inflammation and monitor the clinical condition of the patient and follow up the patient after 28 days. Importantly, even if benefit for the patients is not overt possibly due to the relatively small number of patients studied, the outcomes will better inform the design of larger clinical trials that directly assess the potential of CE-224,535 (and other drugs that also block the P2X7 receptor) to benefit patients with TBI.

Steroids are naturally occurring substances in the body that act as sex hormones and as hormones that control the growth of tissues such as muscle and brain. Usually steroid hormones work by entering a cell and binding to special molecules called receptors. When these receptors are activated by the steroid, they can then turn on the expression in the nucleus of a range of different genes which is specific for that hormone. However, recent studies have shown that steroid hormones can also produce effects on cells rapidly, by mechanisms that do not involve them entering the cell. In these cases the steroids act with receptors on the surface of the cell which bind the hormone at their outer surface, change their shape and then pass on information about the presence of the steroid hormone to the inside of the cell. The cell then responds in an appropriate way. The protein molecules that make up one class of these cell surface receptors bind other small intercellular signalling proteins, called G-proteins, which are used to pass on messages to the rest of the cell from the receptor. Thus, these receptors are also called G-Protein Coupled Receptors or GPCRs. The research proposed in this application aims to understand what functions a novel cell surface GPCR from the fruitfly, Drosophila melanogaster, carries out in the animal and what processes it controls in the cells of the animal. This cell surface receptor is unusual since it can be turned on by both a class of insect steroid hormones, called the ecdysteroids, and by an adrenaline-like molecule, called dopamine. This receptor may be the insect equivalent of a highly unusual vertebrate receptor called the 'gamma-adrenergic receptor'. We do not yet know the structure of this vertebrate receptor but we do know that it can be activated by steroids and that the actions of these steroids can be blocked by dopamine-like molecules. Thus, the findings of this study will be of direct relevance to studies of this latter receptor in vertebrates, including humans. We plan to look at the sites where the steroids and dopamine attach to this fruitfly receptor using molecules tagged with a marker. We will see how easily other molecules, with a similar or different structure, can stop the tagged molecules attaching. This will help us follow how well each substance binds to these sites, give us information about the architecture of the sites and tell us whether the sites overlap or not. We also plan to determine if the signalling pathways, activated by the steroid and dopamine through this receptor, interact or modulate each other. Further, we plan to seek evidence for a function for this insect receptor in some of the rapid cell surface actions of ecdysteroids that have been described in studies on communication between nerve cells and muscles, and in studies on the growth and development of various parts of the insect nervous system. We will see if turning off the receptor in these preparations can block the observed effects of the ecdysteroids. The sequence of the bases in the DNA of all the genes in Drosophila has now been determined but the functions of some of the genes remains unknown and they have been called 'orphan' genes. Thus, we will look to see if any orphan GPCRs with unusual structural and functional properties may also represent cell surface steroid activated receptors. Finally, we plan to use the power of Drosophila genetics to create strains of flies where the novel steroid receptor has been turned off. The behaviour, and other characteristics, of these flies will provide additional information on the function of this receptor in the control of growth and signalling in the insect nervous system. The above studies will provide basic information on the functions of the rapid actions of steroids through cell surface G-protein coupled receptors. They will also provide detailed information on the potential use of this receptor as a new target site for pesticides.