The commonest muscle disease that occurs in patients over the age of 45 years is a muscle wasting disease called inclusion body myositis (IBM). Patients typically develop progressive muscle wasting and weakness that progresses and causes marked disability and ultimately death from immobility over the course of around 10 years. There are no effective treatment for patients with IBM. The precise cause of this muscle disease is not known. However, on muscle biopsies from patients there seems to be a combination of some mild inflammation in the muscle and also an accumulation of abnormal proteins, similar to the accumulated proteins that are seen in the brains of patients with neurodegenerative diseases such as Alzheimer's, fronto-temporal dementia and motor neurone disease. Previous research has indicated that there may be genetic factors that predispose people to getting IBM but the previous studies have been quite small and not conclusive. In this research we have brought together experts in IBM from all over the world including Europe, USA and Australia to generate increased awareness of IBM, define diagnostic criteria, collect clinical information and DNA. Over the last three years we have been able to collect the largest group ever of IBM patients and DNA samples - approximately 950 cases and this number will be over 1000 once this study begins. The patient DNA and muscle tissue has been carefully stored for this work. This very large collection of DNA has put us in a very good position to undertake much more detailed genetic studies than have ever been done before to try and work out what the genetic risks factors and genes are that predispose people to this devastating disease. We plan to use the latest next generation sequencing techniques to unravel all the coding variants (those that alter proteins) that are present in 200 IBM patients DNA samples in comparison with 200 patients that are controls with normal muscles. We will analyze the DNA that we have already extracted from patients muscle tissue as this is the best diagnostic group. We will replicate the variants found in a further 700 IBM cases and over 2200 other controls. We are highly experienced in next generation sequencing technology and this has been strengthened by the recent award of a Wellcome Trust equipment grant to purchase the latest next generation sequencer. Recently we have used these techniques to identify the genetic causes of other neuromuscular disorders. In comparison with other disorders like Alzheimer's disease, where proteins are aggregated in the brain as opposed to the muscle as in IBM, the greatest advancement have been made with the identification of disease genes and genetic risk factors. If we can work out what the key genes are and how these disease causing pathways function, we will pave the way for new therapies and treatments to help patients.

In the UK and elsewhere, people with severe mental illness die prematurely, up to 20 years younger than the general population, a mortality often associated with modifiable medical risk factors. The substantial costs to the health system and the wider economy caused by smoking, obesity, physical inactivity, alcohol misuse and substance abuse are well established. For example, smoking rates among people with a mental illness are three times higher than among the general population. However, while smokers living with severe mental illnesses are just as likely to want to quit as the general population, they are generally more addicted, and face greater barriers to quitting. Similarly, weight gain and obesity are major problems for people with mental health problems, increasing the risk of developing diabetes or cardiovascular diseases, all contributing to low quality of life and exacerbating psychiatric symptoms. Other interwoven and modifiable risk factors associated with the poor physical health of people with mental health problems include low self-esteem, unemployment, loneliness, the low expectations of others, and social exclusion. For a range of social and psychological reasons, including the damage done by stigma, people with mental health problems have relatively limited access to local cultural and natural resources which could improve their physical and mental health. In recent years, greater attention has been focussed on the physical health of people living with mental illnesses but services remain fragmented and uncoordinated. This disconnect may be particularly true in the relationship between statutory health and social care services, and the community and voluntary sector organisations. Moreover, many lifestyle interventions exist that are of potential benefit to people with SMI these are seldom implemented in community settings and there is a lack of evidence on the development of effective interventions to help people with SMI. The CHOICE project aims to build a community coalition of agencies and people across Northern Ireland to maximise the resources, skills and knowledge held collectively. We will use Community-Based Participatory Research (CPBR), a powerful 'bottom-up' approach which uses innovative and inclusive approaches to empower disadvantaged communities and populations in the co- design and implementation of solutions to address health disparities. CBPR helps bridge research and practice by engaging the community to tackle disparities in population health and has been used in diverse and disadvantaged settings as an efficient means of challenging power imbalances. Importantly, our coalition will assist in identifying and exploiting all the assets and resources that exist in our communities but remain generally underused. Working with the experts by experience, we will use arts-based approaches to highlight the experience of living with mental illness, and the relationship between exclusion and physical health. By the end of the project we will have developed a strong community coalition and an agreed strategic plan to improve the lives of people living with mental illness.

Platelets play a pivotal role in the initiation and development of arterial thrombosis, and as such antiplatelet treatments represent the cornerstone therapy for the prevention of myocardial infarction and stroke. Current treatment regimens reduce the risk by ~25%, but patient variability is high, and bleeding remains a challenge. There is therefore a significant drive for safer and more efficacious antiplatelet drugs. To understand the basic biology of thrombosis and develop new antiplatelet drugs, animal models of thrombosis are extensively used globally. These models are non-recovery and involve damage to the blood vessel wall of an anaesthetised animal using ferric chloride (FeCl3) or laser injury, and measurement of thrombus formation using intravital microscopy. The models are limited by lack of standardisation and reproducibility, with large numbers of animals required to provide statistical power. Translation to humans is also limited due to significant species differences in platelet receptor expression, vessel phenotype and haemodynamic profiles. The aim of this project is to REPLACE in-vivo thrombosis models with equivalent human ex-vivo models. The models will comprise of human placental arteries, perfused with human blood at a physiological shear rate. Vascular damage will be initiated by FeCl3 and laser injury, comparable to animal models and thrombus formation imaged using fluorescence microscopy. We have already successfully optimised methods for cold storage (21h post-delivery) and cryopreservation of placental vessels demonstrating maintained vessel viability and endothelial function, maximising accessibility. In this study, the models will be compared in fresh, cold stored (6h and 21h) and cryopreserved vessels. Results obtained using the human ex-vivo model will be validated against equivalent published in-vivo studies testing standard antithrombotic drugs (aspirin, ticagrelor, apixaban) and the model will be established in two of the leading thrombosis groups in the UK (Prof Gibbins, University of Reading; Prof Naseem, University of Leeds) to test interlaboratory variability and further validation. The final part of the project will explore the potential of knocking down individual proteins separately in the artery, platelets and in both, using commercially available PROTACs . Development of human models with the capability to knockdown proteins will enable a larger proportion of in-vivo experiments to be replaced yielding greater 3Rs impact. It would also facilitate investigations to elucidate platelet verses vessel contributions to thrombus formation, furthering mechanistic understanding. In summary, this project will deliver a more ethical and scientifically valid approach to investigate human arterial thrombosis, replacing current in-vivo approaches.