The intestine is one of the largest immune organs in the body. In health, a complex communication network ensures intestinal immune cells peacefully co-exist with the large number of microbes that inhabit the gut. To maintain this tolerance, epithelial cells that form the intestinal wall, underlying immune cells and fibroblasts constantly process signals from their environment. These signals can originate from the sensing of bacteria, or from molecules called cytokines that cells use to communicate with each other. Long-term disruption to any of these communication pathways can result in the development of chronic inflammation and disease. Inflammatory bowel diseases (IBDs) are characterised by a damaging inflammation of the intestinal wall. There is no cure for IBD and patients go through unpredictable periods of relapse and remission. Genes, diet and other environmental factors result in a host-microbial dialogue that is highly individualised across patients. As a consequence, IBDs are highly variable in terms of disease behaviour, location and the response to therapies. Personalised therapies, however, are not standard practise for IBD, reflected by high failure rates of each of the different drugs, with more than 1 out of 2 patients not responding to treatment in the long-term. In recent studies, we grouped patients with IBD that do not respond well to current therapies based on their cellular and molecular characteristics or 'pathotype'. In the proposed programme, we will characterise these IBD pathotypes in more detail and discover new ones. We will examine the cell types, microbes, signalling molecules and clinical features of each pathotype and develop mouse models that accurately reflect disease in these different patient groups. Using these mouse models, we will look at how cytokines control communication between epithelial cells, immune cells and fibroblasts to contribute to disease. Information gained from these studies will be used to design and test candidate therapies. Finally, we will validate the most promising drug candidates in experiments using gut tissues derived from IBD patients belonging to the different pathotypes. Overall, we will generate new information about of the diversity of pathologic processes that drive inflammation in the intestine that can be used as a biological evidence-based guide for improving and personalized therapies in IBD.

Bipolar disorder is a serious mental health problem in which people experience repeated episodes of depression and elated mood. Bipolar disorder affects around 1.2 million people in the UK and costs around £5.2 billion per year. Around 60% of people with bipolar disorder experience problems with their attention and memory, known as cognitive impairment, which greatly affects the ability to work and hold relationships. Currently there are no effective drug treatments for cognitive impairment experienced by people with bipolar disorder. However, drugs which block a type of brain chemical receptor, called the 5HT7 receptor, may be a promising new treatment. The main aim of this study is to understand the effect of a medication called JNJ-18038683, which specifically blocks the 5HT7 receptor, on brain activity and cognitive performance. We will examine the effect of JNJ-18038683 in people with bipolar disorder who show evidence of cognitive impairment and also in healthy people. We plan to do this to determine whether JNJ-18038683 affects brain activity which occurs whilst performing attention and memory tasks, and whether JNJ-18038683 corrects impairments in brain activity and cognitive performance. We plan to recruit 34 people with bipolar disorder and 34 healthy people to take part in the study. Each person taking part in the study will be carefully screened for suitability and will then complete tests of attention and memory function which measures cognitive performance. They will then take 10mg JNJ-18038683 for one week and will be switched to placebo for one week, or vice versa, after a two-week drug free period. Some participants will take JNJ-18038683 first and some will take placebo first, and neither participants nor the staff running the study will know which medication has been taken. We will study the effects of JNJ-18038683 and placebo on brain activity and cognitive performance on day 7 of each treatment period. Brain activity will be measured using a brain scan called magnetic resonance imaging (MRI) which produces very detailed images of the structure and function of the brain. We will examine how JNJ-18038683 and placebo affects the levels of brain activity during the MRI scan by asking participants to complete thinking and mood tasks in the scanner and then analysing the level of brain activity this produces. We plan to assess whether JNJ-18038683 changes brain activity produced during these tasks, and in people with bipolar disorder whether JNJ-18038683 normalises brain activity, by comparing brain activity levels on day 7 of JNJ-18038683 and placebo treatments. We will also assess whether JNJ-18038683 improves cognitive performance by comparing memory and attention test results on day 7 of JNJ-18038683 and placebo treatments. We hope that these results will support the development of further large clinical treatment studies. When the study is complete we will publish its results in scientific journals and communicate this to people with bipolar disorder, mental health professionals and to the general public through press briefings and social media. Overall, we anticipate that this study will allow us to better understand the potential of 5HT7 blockers such as JNJ-18038683 for the treatment of cognitive impairment in people with bipolar disorder which we hope will lead to the development of new treatments.

"The importance of the physical sciences to advance life sciences has never been greater", and inventive chemistry is continuously needed to program, understand and control function. This proposal fits within this context with innovation in the field of radiochemistry to advance molecular imaging. Positron-emission tomography (PET) is a functional and quantitative molecular imaging technology to interrogate biological processes in vivo, facilitate drug discovery and experimental medicine, enable early-stage clinical trials, and guide clinical practice (e.g. cancer and neurological disorders diagnosis, staging, and response to treatment). Combined with other diagnostic tests, this technology can facilitate for example the diagnosis of cancer, evaluate epilepsy, Alzheimer's disease and coronary artery disease. PET scans are routinely performed in the clinic and to support pharmaceutical drug discovery programs. A radiopharmaceutical (radioactive tracer) is required to perform these scans because the technique relies on the emission of gamma rays. These radioactive molecules must be prepared in specialist laboratories that performs radiochemistry with a cyclotron-produced positron emitting radioisotope such as commonly used 18F. Since the half-life of 18F is short (just under 110 minutes), the chemistry involved is challenging. Many groups including our laboratory have focused on novel radiochemical transformations for 18F-labelling because fluorine substitution is frequently encountered in pharmaceutical drugs. Labelling strategies that make use of ubiquitous precursors are the most sought-after, especially if these precursors are amenable to divergent radiochemistries. This is exactly what we will achieve with this project. We propose to develop novel 18F-radiochemistries using ubiquitous primary amines to accelerate PET ligand and radiopharmaceutical discovery. Our strategy consists of converting amines into pyridinium salts that are highly versatile synthetic intermediates acting either as electrophiles or as redox-active precursors. This rich reactivity profile offers the possibility to access a large diversity of 18F-labelled molecules through either direct 18F-fluorination or 18F-fluoroalkylation/arylation from primary amines. Such radiochemistry will streamline access to molecules that are either difficult to label or not possible to label with current technologies. All labelling reactions will be performed on an automated platform that is widely used in the UK and in the world. This aspect of the project is very important to ensure rapid translation of the novel radiochemistry proposed from a research laboratory to the clinic for immediate impact and use to improve patient healthcare, and ultimately for the manufacturing of new PET diagnostics or radioligands.

Immune-mediated inflammatory diseases (IMIDs) are common medical conditions that cause substantial pain, distress, loss of function and early death. They are clinically diverse e.g. by variously targeting the skin, joints, or kidneys, but share some common genetic features, environmental triggers and inflammatory pathologic mechanisms. The IMIDs include rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), Sjogren's syndrome, autoimmune hepatitis and primary biliary cirrhosis. Since the 1990s, biologic drugs and improved treatment strategies have revolutionised the treatment of a significant proportion of people with some IMIDs. However some IMIDs have not really progressed and even in those in which advances are notable, many patients do not yet respond to treatment or lose their responses over time - this in life long incurable diseases. Therefore, there remains great unmet clinical need in the IMID field. One exciting approach to improving outcomes is to apply the principles of precision medicine whereby patients will receive the 'right drug at the right time at the right dose' with minimal chance of having significant toxicity. Bringing precision medicine to IMIDs will require large datasets that integrate clinical information together with complex molecular datasets that can now be generated from the blood and damaged tissues that occur in IMIDs. In theory, by putting this information together we can create a 'molecular map' of a patient that allows very precise treatment decisions to be made that will bring better outcomes at reduced risk. Thus far however most IMID collections of such data have been specified for only one disease leading to a rather narrow approach to the broader inflammation medicine field. This proposal will revolutionise this scenario by bringing together many UK biobank and clinical cohort datasets into one single searchable and analysable entity, lead and coordinated by a consortium called IMIDBio-UK. IMIDBio-UK will generate a virtual information superhighway that will allow unprecedented access to information about IMIDs across the UK. The vision of the IMID-Bio-UK consortium is to harness the power of a rich reserve of biosamples, deeply phenotyped clinical cohorts, and high quality multi-omic data formed from a group of highly successful national stratified medicine programmes. These resources will be made available to researchers to study IMID biology and predict drug response, using molecular markers (biomarkers) to define common and unique mechanisms (endotypes) of disease progression and drug action. This will enable wider, safer use of biologics and new medicines across the IMID spectrum. By bringing together IMID samples and comparing data and clinical practice, we will optimise clinical pathways for common IMIDs, and provide much needed insight into biologic use in rarer or poorly characterised IMIDs, ultimately delivering patient benefit and health care savings.

DPUK is a public-private partnership to accelerate the development of new treatments for dementia. Since inception (2014) DPUK has increased the UK capacity for dementia research through infrastructure development and strategic data collection, leveraging a further £74.4m for dementia research. The second phase of DPUK (DPUK2) focuses on developing UK capacity for dementia experimental medicine. A major challenge in developing new treatments is understanding the mechanisms through which a drug might operate. This involves precision studies where individuals of known vulnerability to specific causes of dementia are recruited to studies of cause-specific mechanistic pathways. These studies are very difficult to do as they require detailed assessment of volunteers before the study begins and standardising all the procedures in centres across the UK. These studies are also high risk in that there is no guarantee of success. DPUK2 addresses these issues head-on at two levels. First it uses the UK's rich legacy in population cohort studies to identify suitable volunteers by using and enhancing existing cohort data. Second it creates a pre-competitive environment that brings together industry, academic and third-sector entities into partnership. This not only shares the costs and risks of experimental medicine (EM) studies, it also shares the benefits amongst a wider spread of stakeholders, each able to exploit the findings. DPUK2 does this through 3 inter-dependent work-streams. 1. The Data Portal (DP): The DP is a world leading end-to-end dementia focused data management solution. It enables large and complex datasets to be accessed remotely from around the globe without compromising data security. The DP is being developed in partnership with Health Data Research UK (HDR UK) so that we can maximise the data available to dementia research. The DP is used to manage all the data and information systems necessary for conducting precision studies. It brings large and complex datasets together in order to test new ideas; it manages personal information securely to enable recruitment to precision studies; it manages many types of data so that genetics, brain imaging, cognitive performance; and questionnaire data can all be analysed together. 2. The Trials Delivery Framework (TDF): The TDF is the vehicle that enables the DPUK2 experimental medicine programme to be efficient. The TDF organises our Clinical Studies Register (CSR) through which cohort members can volunteer for experimental medicine studies. The CSR allows us to contact members to enrich their data in terms of background information, cognitive testing, and where necessary genetics. As part of the CSR, and in partnership with the Alzheimer's Society, we have a PPI programme to understand what best practice is in terms if recruitment to experimental medicine studies. The TDF also enables us to identify centres of excellence across the UK for conducting experimental studies rigorously. This not only assures data quality, but also means that volunteers do not have to travel too far to participate. 3. The EM Incubator: The incubator is where our partners meet to plan and execute the experimental medicine programme. It has three themes; the first is Vascular Health. This is important because so many factors that affect the heart also affect the brain. If any area is likely to have drugs that already exist and could be re-purposed for dementia, this is it.The second theme is Synaptic Health. Here we investigate factors that affect the loss of neuron synapses. This is important because unlike neurons, synapses (the connections between neurons), can be generated, which is critical to learning and maintaining memory. The third area is Neuroimmunology. This is important as inflammation is a systemic problem that is known to affect the brain and might have systemic solutions, and so represents a promising area for new treatments.