What is the problem? Everyone in the UK will have a respiratory illness at some point in their life. We have the best datasets in the world – which should be used to improve respiratory health – but these are currently very difficult to find, access and use. What do we want to do? People in the UK deserve the best respiratory health. We want to make respiratory health better by changing the way the NHS, pharmaceutical companies, charities and researchers use data. How will we do it? We will continue to develop BREATHE (the health data research hub for respiratory health) where trained, approved experts can access respiratory data to benefit patients and the public. We will make it easier for experts to use data in safe and secure ways. How will this benefit patients? BREATHE will support high quality research and cutting-edge innovation that will improve the lives of people living with respiratory conditions in the UK. It is important that patients and the public are involved with this project throughout, including from the very start. This is why there are patient and public members living with respiratory conditions who have worked with us on developing BREATHE and who are committed to delivering BREATHE’s goals.

Summary (up to 4000 characters) To maintain human and animal health, it is extremely important to understand how pathogens like viruses are transmitted and evolve to higher virulence. It is this knowledge that enables employment of effective and sustainable control strategies. Thus, it is necessary to collect, assemble, and analyse highly accurate datasets to determine the short- and long-term effectiveness of disease control approaches, that include biosecurity, genetic selection for disease resistance, and widespread vaccination. In this project, an international, interdisciplinary team investigates the impact of these approaches on the spread and evolution of two avian pathogenic viruses - Marek's disease virus (MDV) and infectious bronchitis virus (IBV) - both of which are primarily controlled by imperfect vaccines. It has been argued that imperfect vaccines like those to MDV and IBV, or host genetic resistance may alter the balance of selection between pathogen transmission and virulence by allowing a few more divergent but still virulent strains to be transmitted at reduced cost. However, these hypotheses have not been proven, and predictive frameworks are lacking for determining the combined influence of host and viral genetics, as well as vaccination on viral transmission and evolution to increased virulence. To address these knowledge gaps, a series of transmission experiments have been designed that utilize unique resources and data from 7,000+ birds under highly controlled conditions. In summary, the primary goal of this research is to collect informative, high-resolution empirical data and use these to build the next generation of data-informed mathematical models of virus transmission and evolutionary dynamics as a function of vaccination status, host genetics, and/or viral mutation rates. We will also address the important and possibly interdependent questions of genome variability and evolution towards increased virulence in vivo. Besides the pure scientific merit of this research, we also strive towards lifting the project to high practical relevance. This requires a whole systems approach that also considers the broader socio-economic and political drivers of disease spread and virulence evolution. We will combine socio-economic studies with mathematical modelling to identify strategies for mitigating MD spread and MDV virulence evolution in sub-Saharan Africa, where poultry production is currently undergoing drastic increases in commercial production, similar to what was observed in the US in the 1960s. We propose the following objectives to achieve scientific excellence and attain broader impact: 1. Determine the influence of imperfect vaccines, host genetics, and viral mutation rate on transmission and evolution to higher virulence. 2. Validate viral genome polymorphisms associated with increased virulence and the ability of the virus to escape immune surveillance. 3. Build data-informed evolutionary-epidemiological simulation models to develop strategies to control the ecology, evolution and economic burden of MD. 4. Disseminate information on MDV and IBV, and the impact of vaccination to poultry producers and the public through training, workshops, online videos, seminars, and various engagement activities

Methacrylic acid (MA) is an important industrial chemical used in the manufacture of transparent polymers such as poly(methyl methacrylate) (PMMA), and is manufactured in large amounts (approximately 3 million tonnes per year). Various approaches have been tested for manufacture of MA and MA esters (MAE) from renewable sources using microorganisms. In this project, together with our industrial partners, we aim to engineer a metabolic pathway for the production of MAE in the yeast Saccharomyces cerevisiae, and to further engineer the host strain to improve tolerance and secretion of this compound and reduce formation of undesirable by-products. We will also test different processes using engineered strains to optimize product formation, including elements such as integration of non-biological catalysts and use of surfactants for product extraction. Ultimately we hope to achieve a clean, efficient and cost effective process for production of MAE, which can be scaled up for commercial use. This project should provide excellent training in synthetic biology, metabolic engineering, and industrial process design, working closely with industrial partners to achieve our goal.

The availability of transgenic rodent (mouse and rat) models of human diseases is revolutionising preclinical research. In particular, non-invasive imaging of rodents with magnetic resonance imaging (MRI) is enabling very powerful studies using the minimum possible number of animals. In this project we are concerned with common cardiovascular diseases such as high blood pressure, diabetes and arterial disease, which are major causes of death in the Western world. Of particular interest are the function of the heart, and blood flow in the major arteries. One problem with MRI is the length of time it can take to collect the images. For example, to collect movies of how the heart pumps and the blood flows, scanning can take more than an hour with standard techniques. We will develop advanced scanning and image processing techniques to reduce the time that individual animals are in the MRI scanner. In order to develop our imaging techniques without using live animals, we will first build a rodent heart simulator that mimics the pumping action of the heart. This project directly addresses the 3R’s of biomedical research (www.nc3rs.org.uk): REDUCTION of animal numbers and scanning time, REFINEMENT of experiments, and REPLACEMENT of animals with the heart simulator for development purposes.