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.

Pseudomonas aeruginosa (Pseudomonas) is a bacteria which causes a wide variety of infections, including corneal (eye), lung and blood, resulting in significant disability and death worldwide. A recent surge in antibiotic-resistant Pseudomonas has prompted the World Health Organisation to advise new treatments must be developed as a 'high priority'. Recovery for many patients remains very poor even if their condition is treatable with antibiotics. For those with corneal (transparent window at the front the eye) infections, significant damage and scarring can lead to blindness. In Pseudomonas infections with poor outcomes it has been established that the bacteria inject a toxin, called Exotoxin U (ExoU), into human cells. ExoU rapidly kills the cells including immune cells sent to fight the infection. The bacteria evade the immune system to continue multiplying and causing damage. Inhibiting ExoU could provide a new treatment to reduce the severity, disability and death caused by this bacteria. We have identified 25 promising drugs which specifically inhibit ExoU. In test-tube models of corneal infections, the drugs reduce damage and show protective effects which help the cells heal. This occurs even at very low concentrations. Our data suggests they can be combined with antibiotics to improve these results. Significant research is required prior to human trials. This includes testing different concentrations, combinations, assessing how well they get to the site of infection, and testing them in clinically-relevant animal models. Protocols for administration are also required, including strength, frequency and length of the course. Demonstrating they work for infections in other organs, such as the lung, would prove they could be developed to treat and benefit more patients. My fellowship project will build on our initial work, with the following aims and objectives: 1) I will evaluate the ExoU inhibiting drugs in scratch and infection cell models, primarily in eye cells, but also lung cells to see if they will work in these too. Different concentrations and combinations will be tested, with and without antibiotics. Results will demonstrate their potential and help develop the treatment protocols. 2) I will measure the concentration of the ExoU inhibiting drugs that get to the site of infection. I will utilise a model which uses a donor human cornea attached to a glass artificial model of the anterior chamber of the eye (the front part which contains fluid). The drug, as an eye-drop, will be applied to the surface, and samples of the fluid within will be taken at different time-points. The concentration of drug in these samples will be measured. This is important information which will aid the development of the treatment protocols and advance the drugs towards human trials. 3) I will evaluate the ExoU inhibiting drugs in a more advanced infection model. Pig corneas (by-products of the food industry) will be infected with Pseudomonas and treated with the ExoU inhibitors using the protocols developed in objectives 1 and 2. This will help identify the most promising drugs and refine the treatment protocol which will be used in further experiments. Conducting this experiment will significantly reduce the number of animals required in subsequent experiments. 4) When I have identified the two best drugs and protocols, I will evaluate these further in a mouse model of corneal infection. This work will be conducted with my collaborators in the United States who have an ethically approved model and the expertise. These experiments will provide the necessary data, including the safety data, which we will require to proceed to human clinical trials. My project will significantly develop the knowledge required to progress these ExoU inhibiting drugs towards human trials. The ultimate aim is that the drugs will be used to treat patients with Pseudomonas infections to improve their recovery and overall outcome.

Definition: A rapidly developing area at the interfaces of engineering/physical sciences, life sciences and medicine. Includes:- cell therapies (including stem cells), three dimensional cell/ matrix constructs, bioactive scaffolds, regenerative devices, in vitro tissue models for drug discovery and pre-clinical research.Social and economic needs include:Increased longevity of the ageing population with expectations of an active lifestyle and government requirements for a longer working life.Need to reduce healthcare costs, shorten hospital stays and achieve more rapid rehabilitationAn emergent disruptive industrial sector at the interface between pharmaceutical and medical devicesRequirement for relevant laboratory biological systems for screening and selection of drugs at theearly development stage, coupled with Reduction, Refinement, Replacement of in vivo testing. Translational barriers and industry needs: The tissue engineering/ regenerative medicine industry needs an increase in the number of trained multidisciplinary personnel to translate basic research, deliver new product developments, enhance manufacturing and processing capacity, to develop preclinical test methodologies and to develop standards and work within a dynamic regulatory environment. Evidence from N8 industry workshop on regenerative medicine.Academic needs: A rapidly emerging internationally competitive interdisciplinary area requiring new blood ---------------------

Kidney failure can have a devastating impact on patients' lives. Transplantation offers much better long-term survival prospects compared to dialysis, but there is an acute shortage of donors. Compared to deceased kidney donation, living-donor kidney donation (LKD) has even better long-term patient and transplant outcomes. However, medical incompatibility, for example, may prevent a living donor from donating a kidney to a loved one who is in need. Kidney Exchange Programmes (KEPs) help to increase LKD by allowing recipients who require a kidney transplant, and who have a willing but medically incompatible donor, to "swap" their donor with that of another recipient, leading to a cycle of transplants. Altruistic donors may trigger chains of transplants that can also benefit multiple recipients. The UK Living Kidney Sharing Scheme (UKLKSS), which is operated by NHS Blood and Transplant (NHSBT), is the largest KEP in Europe. Algorithms developed by Manlove and his colleagues have been used by NHSBT to find optimal solutions for UKLKSS matching runs every quarter since 2008. There are several ways in which the UKLKSS can be expanded and strengthened in the future, to facilitate better matches and more transplants, as follows: 1. Cycles and chains are currently restricted in length for logistical reasons. Allowing longer cycles and chains than at present will lead to more kidney transplants. 2. International collaboration between the UK and other countries will lead to more transplantation opportunities, particularly for highly sensitised (hard to match) recipients. 3. In the presence of longer cycles and chains, and international collaboration, the existing interpretation of an "optimal" solution will no longer be valid. Conducting simulations will allow NHSBT to determine exactly what they wish to optimise in the light of long-term effects on simulated data. Delivering these enhancements will involve tackling the following complex research challenges: (RC1): design algorithms for larger pools and longer cycles / chains. As the underlying computational problem of finding an optimal set of kidney exchanges is intractable, advanced techniques are required to find a solution efficiently. (RC2): design algorithms for international kidney exchange. When multiple countries are participating in an international KEP, key considerations of fairness and stability become important. (RC3): design algorithms to cope with changes to optimality criteria. A small change to an optimality objective can necessitate significant changes to the algorithm to find an optimal solution. (RC4): create a dynamic dataset generator, producing instances that reflect real-world characteristics. This will give realistic estimates of the effects of different optimality criteria for NHSBT. The proposed project will meet all these challenges via a new collaboration between Glasgow and Durham. This will provide a synergy between the expertise of Manlove in matching problems and kidney exchange, and that of Paulusma in game-theoretic aspects of matching problems and international kidney exchange. The main resources requested are Postdoctoral Research Associates at Glasgow and Durham, and a Research Software Engineer at Glasgow. The project partner NHSBT will be a key member of the project team. The project will also benefit from the expertise of the following visiting researchers: Maxence Delorme (Tilburg University, operational research), Péter Biró and Márton Benedek (KRTK Budapest, algorithmic game theory). The work programme comprises three interconnected work packages, as follows: WP1: design of new algorithms for national KEPs, using advanced integer programming techniques. WP2: design of new algorithms for international KEPs, using techniques from cooperative game theory. WP3: software implementation and experimental evaluation, which will include building new software for the UKLKSS, realising the impact of this project.

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.