Nucleic acid therapeutics (NATs) offer great potential to treat rare diseases (RDs) by addressing their genetic causes in a target-specific manner. The exponential increase in NAT clinical trials in the last few years clearly demonstrates the role of these molecules in translational research and unique opportunities for investigator-led preclinical and clinical studies, in which the UK has particular track record strengths. To further promote the development of NATs for RD patients in the UK, we are creating the node entitled, 'Establishing a UK Platform for the Development of Nucleic Acid Therapy for Rare Disease' (UPNAT). UPNAT will bring together relevant stakeholders, comprising of scientists, clinicians, geneticists, trainees, patient advocacy groups and charities, industrial partners, international non-profit organizations and regulatory bodies, to establish and coordinate a national network that will facilitate the exploitation of the rapid development of NATs. UPNAT intends to address a number of challenges that NAT research and development is currently encountering in the RD field within the UK, including 1) a lack of a national infrastructure for cross-disciplinary knowledge exchange and expertise sharing between centres leading NAT preclinical and clinical development; 2) a clear path for systematically linking patients carrying unique mutations to NAT expertise; and 3) the need for continuous dialogue between regulators and researchers to streamline the process of regulatory approvals, monitoring of outcomes, and accelerating the clinical translation of RD-specific NATs. To tackle these challenges, UPNAT will create the following networking opportunities: 1) scientific symposia to promote cross-disciplinary knowledge exchange between researchers, clinical and industry stakeholders; 2) webinars and activities between patient advocacy groups, charities, and researchers to promote public engagement; 3) training schemes to educate and equip the next generation of scientists and clinicians with the knowledge and skills to lead future NAT research programs. The node encompasses three complementary projects, to address the overall objectives and crucial bottlenecks. These projects focus on 1) Target selection, NAT strategy design and pre-clinical development; 2) Enhancing UK's capability in NAT scale-up synthesis and pilot toxicology studies tailored for RD; 3) NAT clinical trial design and regulatory approval. Collectively these work packages will enable a robust framework for the design, development, and clinical translation of NAT to be adopted by RD centres in the UK. UPNAT will focus on areas of unique strength in rare paediatric and adult disorders, including six paediatric highly specialised services provided by the partner organisations in London, Oxford, Cambridge, Birmingham, Liverpool and Sheffield, and the adult expert centres at the University College London (UCL) Institute of Ophthalmology, Institute of Neurology, Moorfields Eye Hospital and University College Hospital. The node will be focused on neurological, neurodegenerative, metabolic and ophthalmological diseases which are uniquely conducive for NAT applications and remain open to other disease areas as NAT technology rapidly advances and Node develops. UPNAT will be led by investigators and collaborators from UCL Great Ormond Street Institute of Child Health, Institute of Ophthalmology, Institute of Neurology, Great Ormond Street Hospital (GOSH), Moorfields Eye Hospital, UKRI NATA (Oxford) and investigators from Oxford, Cambridge and Birmingham. Node members will work in partnership with Genomics England, five NIHR BRCs (GOSH, UCLH, Moorfields, Oxford and Cambridge), industry, patient advocacy groups and charities, the UK regulators, and the international consortia on NAT in RD. Collectively, we are well equipped and determined to maximise the transformative potential NATs offer for the RD patient community within the UK and beyond.

Lung diseases such as Asthma and Chronic Obstructive Pulmonary Disease affect one in five people in the UK and kill someone every 5 minutes. The number of patients with these lung diseases was increasing in the NHS even before COVID-19. We are also learning about serious long-term effects of COVID-19 that will add to the existing burden on the NHS. There have been huge advances in technologies that allow scientists to see inside the lungs and measure what we breathe out. While this information has taught us quite a lot, it is still very difficult to combine different sources of information and turn it into new or improved treatments. Getting that useful information out of large amounts of medical test results requires sophisticated physics-based mathematical and statistical models run on powerful computers - a combination of techniques called data-driven biophysical multiscale modelling. The ability to develop those kinds of models will allow us to better understand how diseases start and how they progress. Our BIOREME network will support new research that uses these techniques to mimic biological and mechanical processes that occur throughout the lung. Using the information from thousands of lung tests, the idea is then to get these models to mimic real diseased lungs. In order to improve and build trust in these models, some of our projects will be focused on comparing their outputs to results from other lung tests. Medical scientists can then use such models to test what might happen in a particular type of lung disease, and to investigate possible responses to new treatments before testing these in patients. Most importantly, this will lead to the design of new drugs and improved trials for new treatments. The first step will be to get medics, imaging experts and mathematicians together with industry and patient group representatives to decide on which specific research areas to prioritise, where this form of modelling will make the most difference. This NetworkPlus award will then allow us to organise multiple events, in different formats, designed to help researchers to collaborate, and to come up with the best initial projects to help achieve our goals. We will then help the researchers to develop these into larger projects that will attract funding from other sources and continue the research into the future. Even after this funding runs out, BIOREME will provide a lively forum for lung researchers to continue solving problems using these advanced computational tools. Finally, BIOREME will support outreach activities to engage and educate communities and young people in the role that mathematics can play in medicine and healthcare, and to inspire a new generation of respiratory scientists from diverse backgrounds.

Alzheimer's disease (AD) is often mis-perceived as a disorder largely or solely of memory. However the disease also affects the visual areas of the brain leading to problems seeing what and where things are. Dementia-related visual impairment tends to be neglected, partly because people assume any problems are due to the eyes rather than the brain, and because it occurs at a point when language and other skills are too impaired for the person with dementia to explain the perceptual problems they are having. Visual problems are also often mis-attributed to poor memory (e.g. a person with AD failing to recognize a family member in a photo may be thought to have "forgotten" the person, when in fact they may simply be unable to perceive the face clearly). Visual impairment in AD has received increased attention recently with the identification of the syndrome Posterior Cortical Atrophy (PCA) which is typically caused by AD but presents with dramatic impairment of vision not memory, as experienced and described by the author Terry Pratchett in his documentary Living with Alzheimer's. Very few studies have explored the effect of impaired vision upon people with dementia or their caregivers. A motivation for improving our understanding of how people with AD see the world is that the limited number of small studies which have been conducted suggest that even simple changes to the environment (e.g. changing the colour of tableware from white to red) can compensate for vision problems in people with AD and lead to improved functioning and health (e.g. better eating and drinking). The project objective is to demonstrate that helping AD patients to interact more successfully with their visual environment at home can have a significant positive impact upon the wellbeing and quality of life of both patients and carers. The project will involve 50 people with PCA, 150 with typical Alzheimer's disease and 100 healthy volunteers. The impact of visual aids and strategies will be measured at three time-points over the course of one year, with a staggered start to enable comparisons of quality of life in those with and without the intervention. The success of the project will be judged primarily using established measures of quality of life, caregiver burden, everyday abilities, and behavioural and psychological wellbeing. However, the design of the visual aids and compensatory strategies themselves will be based upon a combination of patient/carer interviews (qualitative evidence) and cutting-edge scientific understanding of the nature of visual impairments caused by conditions such as Alzheimer's disease (quantitative evidence). This quantitative evidence will be gathered through studies of patient's visual skills and eye movements, and their ability to move around a purpose-built laboratory environment, before the main study commences in patients' own homes. Another important aspect of the project is the involvement of people with PCA, who experience AD-related visual loss but without the loss of memory and insight seen in typical AD. These individuals with PCA offer a new and unique perspective on the AD patient's view of the world. Their experiences of care homes and day hospitals draws attention to the fact that many current social and behavioural interventions for people with dementia may be limited in their effectiveness by over-reliance upon visual information and by a systemic failure to recognize visual impairment in many service users. The research brings together experts in the fields of dementia, engineering, social science, social work, occupational therapy and ophthalmology. This interdisciplinary research team will work closely with the DeNDRoN ENRICH scheme and project advisors in the 3rd sector and industry specializing in dementia and vision loss (e.g. Thomas Pocklington Trust, Dementia and Sight Loss Interest Group, ARUP, CDRAKE) to improve the study and implement its findings.

When teenagers get a good night's sleep, they are more likely to be able to concentrate, regulate their emotions and behaviours, problem-solve, learn and succeed at school, and avoid difficulties with anxiety and depression. Teenagers are naturally vulnerable to problems with sleep, because of multiple biological, psychological, and social changes. Although some teenagers will be lucky to avoid problems with their sleep, up to two thirds do not receive the recommended 8-10 hours sleep. Furthermore, many teenagers experience several unpleasant consequences of this lack of sleep. For some young people, the experience of disturbed sleep as a teenager can lead to long-term difficulties with mental health, particularly depression. Experiencing depression is not uncommon during the teenage years, with an estimated 154,000 10-19 year olds meeting diagnostic criteria for depression. Difficulties with depression can lead to difficulties at school and with friendships, as well as commonly presenting with self-harm and suicidal behaviours. Negative thinking patterns, or 'cognitions', have long been theorised to play a key role in the maintenance of various mental health problems, triggering unhelpful cycles of behaviour as well as causing distress. There is evidence that this may be the case for both insomnia and depression. There is also preliminary evidence that negative cognitions may explain why sleep problems can lead to depression, with it being theorised that sleep-specific cognitions can trigger more generalised negative thoughts about the world. Psychological treatments for sleep problems have been found to improve both sleep and mood in adults and young people, and adult psychological models of insomnia propose that these treatments help generate positive and helpful thoughts about sleep, which may generalise to positive and helpful thoughts more broadly. However, this has rarely been tested, and it is not currently known if this theory can be applied to depression or teenagers. We would like to find out: The proposed research uses an intervention design to better understand 1) how sleep and depression are linked in teenagers, 2) why improving sleep can also reduce depression, and 3) whether negative thoughts about sleep can be changed and interrupt other negative thoughts. Workshops using evidence-based techniques for improving sleep will be delivered in schools by external mental health practitioners. Workshop content will include how to create a good sleep environment and setting optimal bedtimes and waketimes as well as follow-up sessions to check in and help problem-solve. Sleep, mood and cognition will be measured pre- and post-intervention, and at a follow-up, to measure change. The study design will also allow us to examine whether offering sleep interventions in schools could improve both sleep and depression, and whether it is a scalable solution that should be tested and evaluated on a larger scale. Why this matters: This research is important because it will help us to understand how and why teenagers' sleep is crucially linked to their mood and wellbeing. The findings will provide evidence of how best to support teenagers to improve their sleep quality and quantity, with potential short- and long-term improvements in their wellbeing. To ensure that the research has long-term benefits for society, the work is being conducted within one of the recently provisioned services providing school-based mental health support, meaning that it could be scaled up nationally. The research has the potential to dramatically affect the way that schools and parents can support young people's wellbeing and to significantly decrease problems with sleep and depression as a consequence. This would improve the quality of life of teenagers across the UK and decrease the substantial societal costs associated with long-term mental health problems.

This application brings together two world-renowned research- and educational-focused Universities in a unique collaboration to create an interdisciplinary training approach to meet challenges in healthcare. With complementary strengths in basic physical sciences, engineering and clinical translation, close strategic and geographical links and a CDT embedded within a top-rated teaching hospital, the KCL/ICL alliance is superbly placed to train the next generation of imaging scientists and research leaders. The CDT will provide a unique interdisciplinary training program to develop the skills for creating innovative technical solutions through integration of the physical sciences, engineering and biological and clinical disciplines. The Centre will be integrated into a large research portfolio in medical imaging funded through EPSRC/Wellcome Trust Medical Engineering Centres, MRC centres, the CRUK/EPSRC Cancer Imaging Centres, and the BHF Centres of Excellence. In order to foster clinical translation of research, the CDT will be linked into two Academic Health Science Centres and NIHR-Biomedical Research Centres. The CDT will create a critical mass of teachers and researchers to establish an interdisciplinary training program by bringing together students from different disciplines to work on research topics in medical imaging. The CDT will feature a 1 + 3 years MRes+PhD structure and will manage the students as a single cohort. We have developed the different phases of the PhD programme, i.e. Recruitment, MRes, PhD and Alumni, to achieve the highest quality in training, research and career development for the individual student. We place a strong emphasis on clinical translation, therefore the CDT will continue with a formal training programme in clinical applications in parallel to the PhD projects. In addition, the teaching location of the Centre in a dedicated, newly-refurbished CDT teaching hub within a world-class teaching hospital engenders strong links with the NHS and provides further enhanced opportunities for clinical translation. The first and foremost goal of this CDT will be to provide the highest quality supervision for individual students. To achieve this, we will combine the experience of senior supervisors with the energy and development of more junior academics. At the start of the CDT, we will be defining PhD projects from 60 supervisors with world-leading research expertise in the underpinning of the multidisciplinary themes in medical imaging. All of those scientists have a track record in PhD supervision and delivering research funded by research councils. We have also identified clinical champions in three major disease areas (Cardiology, Oncology, Neuro) who will organize training in clinical application. This training is designed to forge interactions between scientists and clinicians. It will provide students with valuable contacts with whom they can discuss clinical implications of their PhD research. The CDT will provide training of a new generation of scientists with skills in interdisciplinary research, clinical translation and entrepreneurship. The focus of both graduate training and the individual student research projects will be to innovate medical imaging technologies in the care cycle of patients across a range of diseases. Another central theme within the program will be training to translate innovations into commercial products. For this, we will leverage our strong industrial links and have obtained financial commitment for more than 25 co-funded industrial CDT studentships from various industrial partners. The partners, including new UK-based SMEs and start-up companies, will also provide internships to enable career paths into industry.