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Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Sarcopenia is an age-related loss of skeletal muscle mass and strength. It is characterised by muscle fibre atrophy (decreased muscle fibre size) and reduced muscle function linked to increase of the presence of non-muscle cells, like fat, within the muscle and disrupted muscle repair. Sarcopenia leads to poor balance, falls and fractures and increased morbidity and mortality in our ageing population. As the ageing population increases, it is important to identify the mechanisms responsible for this age-related muscle loss. The molecular factors responsible for sarcopenia are not fully understood, however changes in the expression of genes have been implicated in sarcopenia. MicroRNAs (miRNAs, miRs) are small RNA molecules that regulate gene expression. Each microRNA is predicted to regulate the expression of up to several hundred genes. Expression of numerous microRNAs and their target genes changes with age or in diseases. This makes microRNAs very strong candidates for therapeutic targets for sarcopenia and other age-related disorders, for example by controlling their levels by using molecules that mimic their behaviour. In preliminary data the applicant has shown that that the levels of microRNAs, important for muscle function, change in muscle with age. This new research proposes that the age-related changes in microRNA abundance are a major contributing factor to the muscle loss process. Using cell culture and model organism systems, the levels of these small molecules (microRNAs) will be manipulated in muscle cells and tissues and the effects on muscle wasting will be examined. Concurrently, the potential of miRNA-based intervention to prevent, delay or treat sarcopenia will be established. The first objective will determine the set of muscle-specific microRNAs that are changed in the muscle tissue of old mice compared with adult mice. The second objective will confirm important microRNA target genes in muscle and characterise the details of the interactions of microRNAs and the specific genes they regulate in the context of loss of muscle mass and function. The final aim of the project will examine the potential of microRNA mimics and antagomiRs (small molecules that increase or decrease of the microRNA levels, respectively) in preventing age-related loss of muscle using a mouse model organism. This project is important to strengthen our knowledge about the molecular basis of sarcopenia and is likely to lead to the design of novel therapeutic approaches to prevent, delay or treat age-related skeletal muscle wasting.

Nuclear physics research is undergoing a transformation. For a hundred years, atomic nuclei have been probed by collisions between stable beams and stable targets, with just a small number of radioactive isotopes being available. Now, building on steady progress over the past 20 years, it is at last becoming possible to generate intense beams of a wide range of short-lived isotopes, so-called "radioactive beams". This enables us vastly to expand the scope of experimental nuclear research. For example, it is now realistic to plan to study in the laboratory a range of nuclear reactions that take place in exploding stars. Thereby, we will be able to understand how the chemical elements that we find on Earth were formed and distributed through the Universe. At the core of our experimental research is our strong participation at leading international radioactive-beam facilities. While we are now contributing, or planning to contribute, to substantial technical developments at these facilities, the present grant request is focused on the exploitation of the capabilities that are now becoming available. Experimental progress is intimately linked with theory, where novel and practical approaches are a hallmark of the Surrey group. An outstanding feature, which is key to our group's research plans and is unique in the UK, is our powerful blend of theoretical and experimental capability. Our science goals are aligned with current STFC strategy for nuclear physics, as expressed in detail through the Nuclear Physics Advisory Panel. We wish to understand the boundaries of nuclear existence, i.e. the limiting conditions that enable neutrons and protons to bind together to form nuclei. Under such conditions, the nuclear system is in a delicate state and shows unusual phenomena. It is very sensitive to the properties of the nuclear force. For example, weakly bound neutrons can orbit their parent nucleus at remarkably large distances. This is already known, and our group made key contributions to this knowledge. What is unknown is whether, and to what extent, the neutrons and protons can show different collective behaviours. Also unknown, for most elements, is how many neutrons can bind to a given number of protons. It is features such as these that determine how stars explode. To tackle these problems, we need a more sophisticated understanding of the nuclear force, and we need experimental information about nuclei with unusual combinations of neutrons and protons to test our theoretical ideas and models. Therefore, theory and experiment go hand-in-hand as we push forward towards the nuclear limits. An overview of nuclear binding reveals that about one half of predicted nuclei have never been observed, and the vast majority of this unknown territory involves nuclei with an excess of neutrons. Much of our activity addresses this "neutron-rich" territory, exploiting the new capabilities with radioactive beams. Our principal motivation is the basic science, and we contribute strongly to the world sum of knowledge and understanding. Nevertheless, there are more-tangible benefits. For example, our radiation-detector advances can be incorporated in medical diagnosis and treatment. In addition, we provide an excellent training environment for our research students and staff, many of whom go on to work in the nuclear power industry, helping to fill the current skills gap. On a more adventurous note, our special interest in nuclear isomers (energy traps) could lead to novel energy applications. Furthermore, we have a keen interest in sharing our specialist knowledge with a wide audience, and we already have an enviable track record with the media.

Acute Respiratory Distress Syndrome (ARDS) is a severe clinical syndrom that affects 20% of all critically ill patients in intensive care. Unfortunately, around 30-50% of these people will die from the condition and the quality of life of the survivers can be seriously reduced due to the consequent chronic lung problems.There is no effective treatments for this condition at this time and therefore new medicines are urgently needed. ARDS is characterised by an excessive and disregulated inflammation in the lung that leads to inappropriate infiltration of immune cells, lungs fill with water and fail to maintain its main function - breathing. In order to breath these patients require mechanical ventilation. ARDS results from multiple causes, although pneumonia induced ARDS is the most common and the most devastating. Inflammation is the way in which the body reacts to infection, irritation or other injury. Normally, inflammation is one way the body heals and copes with the infection, however, when disregulated in certain condition such as ARDS it can lead to severe damages and impair of the the lung function. Immune cells called macrophages have increasingly been recognized to play a key role in the development and resolution of ARDS functioning as a coordinators of inflammatory responses. Recently more and more attention of clinicians and basic scientists working in the field of ARDS research is drawn to cell-based therapies. A key advantage of cell based therapy compared to pharmacologic treatment is that cells can actively respond to the local microenvironment and exert multiple beneficial effects, modulating several injurious and reparative pathways in this complex disease process. One of the most promising candidate for a cell based therapy for ARDS are cells termed Mesenchymal Stem Cells (MSC), which represent one kind of adult stem cells (can be easily isolated from tissues of adult patients or healthy volunteers), because of this there is no ethical issues that are related to use of embryonic tissues. MSC could easily be propagated and manipulated under laboratory conditions and have capacity to differentiate into multiple different cell types of the body. Importantly, long term research has shown their safety in terms of developing tumors. Multiple preclinical animal studies conducted by our group as well as by other investigators showed that MSC indeed have protective effect when administered as a treatment for ARDS. Among several beneficial effects, their administration always is associated with drastically reduced inflammation, however the mechanisms of this phenomenon are still unclear and data on their interaction with the immune cells of the lung remain unsufficient and controversial. To translate MSC into the clinical practice it is essential that we have more precise understanding of their mechanism of action. The main question we are keen to address in the proposed research is: how MSC treatment influence the lung macrophages? What alterations do MSC induce in their functions and what molecular mechanisms mediate those changes. Based on our preliminary data and results from other studies we have reasons to hypothesize that MSC will promote polarization of macrophages towards the state in which they will supress the inflammation and promote the resolution of ARDS- so called "alternatively activated macrophages" or M2 macrophages. The mechanistic data from this study will bring development of new therapy on the MSC basis closer to the patients. Additionally, it will broaden the existing knowledge of lung macrophage biology and their role in the resolution of ARDS which could lead to other new treatments. Importantly, findings from the proposed study may also have relevance for other macrophage dependent inflammatory conditions.

The societal needs such as helping elderly and rapid technological advances have transformed robotics in recent years. Making robots autonomous and at the same time able to interact safely with real world objects is desired in order to extend their range of applications to highly interactive tasks such as caring for the elderly. However, attaining robots capable of doing such tasks is challenging as the environmental model they often use is incomplete, which underlines the importance of sensors to obtain information at a sufficient rate to deal with external change. In robotics, the sensing modality par excellence so far has been vision in its multiple forms, for example lasers, or simply stereoscopic arrangements of conventional cameras. On other hand the animal world uses a wider variety of sensory modalities. The tactile/touch sensing is particularly important as many of the interactive tasks involve physical contact which carry precious information that is exploited by biological brains and ought to be exploited by robots to ensure adaptive behaviour. However, the absence of suitable tactile skin technology makes this task difficult. PRINTSKIN will develop a robust ultra-flexible tactile skin and endow state-of-the-art robotic hand with the tactile skin and validate the skin by using tactile information from large areas of robot hands to handle daily object with different curvatures. The tactile skin will be benchmarked against available semi-rigid skins such as iCub skin from EU project ROBOSKIN and Hex-O-Skin. The skin will be validated on at least two different industrial robotic hands (Shadow Hand and i-Limb) that are used in dexterous manipulation and prosthetics. The robust ultra-thin tactile skin will be developed using an innovative methodology involving printing of high-mobility materials such as silicon on ultra-flexible substrates such as polyimide. The tactile skin will have solid-state sensors (touch, temperature) and electronics printed on ultra-flexible substrates such as polyimide. The silicon-nanowires based ultra-thin active-matrix electronics in the backplane will be covered with a replaceable soft transducer layer. Integration of electronic and sensing modules on a foil or as stack of foils will be explored. 'Truly bottom-up approach' is the distinguishing feature of PRINTSKIN methodology as the development of tactile skin will begin with atom by atom synthesis of nanowires and finish with the development of tactile skin system - much like the way nature uses proteins and macromolecules to construct complex biological systems. This new technological platform to print tactile skin will enable an entirely new generation of high-performance and cost-effective systems on flexible substrates. Fabrication by printing will have important implications for cost-effective integration over large areas and on nonconventional substrates, such as plastic or paper. Printing of high-performance electronics is also appealing for mask-less approach, reduced material wastage, and scalability to large area. The proposed programme thus has the potential to emulate yet another revolution in the electronics industry and trigger transformation in various sectors including, robotics, healthcare, and wearable electronics.

The harnessing of one's own immune system to treat a cancer, termed tumour immunotherapy, is an extremely attractive proposition because of the potential for combining high selectivity with low toxicity. Tumour immunotherapy has progressed significantly in recent years with improved understanding of how to boost the normally weak immune response to tumours. Nevertheless, there is considerable need for more improvements to ensure this form of treatment is more widely and effectively applied. Successful immunotherapy depends on immune cells, such as killer T lymphocytes, becoming activated and homing to the tumour. However, tumour blood vessels limit access of T lymphocytes to the tumour. We have found that T lymphocytes are better equipped to control tumour growth when they express the homing molecule L-selectin. We predict this is because L-selectin expression factilitates access of killer T cells to the tumour where they can deliver their lethal hit. The aim of this proposal is to study the properties of these L-selectin enhanced T lymphocytes and to determine whether they could be used to treat tumours. The potential long-term benefit of this work is that it will direct novel strategies for improving the clinical application of tumour immunotherapy.

Parkinson's disease is caused by the degeneration of nerve cells in part of the brain; leading to the loss of dopamine, a chemical messenger which plays a vital role in coordinating body movement. In early stages of PD, oral levadopa (L-DOPA) medication is effective in managing the symptoms that include tremor, muscle stiffness and slow physical movement. However, the body progressively loses its ability to convert L-DOPA to dopamine thereby reducing its effectiveness and leading to the development of uncontrolled motor function. Oxford BioMedica has developed a 'once-only' gene therapy approach to treat individuals with PD called OXB-102 that is administered once to the target region in the brain where it converts cells into a replacement dopamine factory. In essence, OXB-102 replaces a patient’s own lost source of the neurotransmitter analogous to the natural dopamine supply in the absence of PD.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Invasive fungal infections are uncommon in healthy individuals however several conditions can greatly increase the risk of developing these infections. For example patients undergoing immunosuppressive therapies, either following organ transplant or for the treatment of diseases such as cancer and autoimmune conditions, are much more likely to develop invasive fungal infections. People with a suppressed immune system either as a result of infections such as HIV or due to inherited mutations in key proteins that regulate immunity are also at much greater risk of acquiring fungal infections. In these patient groups when invasive fungal infections occur they are difficult to treat and have a high mortality rate. This represents an increasing problem as the numbers of people in high-risk groups grows and as resistance to existing antifungals increases. Understanding how the immune system detects and responds to fungal pathogens is therefore an important issue. Following infection, one of the first cell types to detect fungal pathogens are specialized cells in the immune system termed antigen-presenting cells (APCs). Once these cells sense the presence of a fungal pathogen they undertake several functions, key amongst which is the production of cytokines, small proteins that are released from immune cells and that are required to co-ordinate the immune response. APCs are able to detect fungal pathogens as they express certain specialized receptors that are specific for molecules that are found on the surface of fungal pathogens but not on the body's own cells. One such receptor is a protein called dectin-1. The relevance of dectin-1 to fungal infection has been demonstrated by the observations that both dectin-1 knockout mice and people that carry an inactivating mutation in the dectin-1 gene are more sensitive to fungal infection. In the research outlined in this proposal we will use a variety of techniques to study the way in which the activation of dectin-1 promotes the required cellular response and controls the production of cytokines. Key to this is understanding how dectin-1 affects intracellular signaling networks, many of which are controlled by a process known as protein phosphorylation. These processes are essential for the cell to translate the detection of a fungal pathogen by dectin-1 into the correct immune response. A major part of this study will be to use sate of the art mass spectrometry methods to map global changes in protein phosphorylation that occur inside the cell following the activation of dectin-1. This will allow us to build up a picture of the signaling networks activated. We will then examine the contribution of specific parts of this network to the control of cytokine production. This work will increase our understanding of how the immune system deals with fungal infections, and may suggest ways in which the immune system could be targeted to increase its ability to combat fungal infections. In addition several of the cytokines that are induced by fungal pathogens can, in other circumstances, have pathological roles such as in autoimmune diseases like arthritis. Understanding how their production is controlled therefore also has wider implications for interpreting how the immune system functions and for future drug development programs for a number of immune related diseases.

The Medical Research Council funded North West Hub for Trials Methodology Research (NWHTMR) is a collaboration which brings together experts in clinical trials research from the Universities of Liverpool, Lancaster, Bangor and Manchester. Clinical trials are studies conducted in patients to evaluate the potential benefits (and risks) that new treatments could offer. They provide the 'gold standard' evidence base for informing and improving future patient care. The Hub has experts in medical statistics, clinical trials methods, pharmacoeconomics (drugs are compared for their value), sociology and clinical psychology. The Mission of the Hub is to create a world-class centre where methods used in clinical trials can be investigated. The overall aim is to improve patient care by making sure we test, use and develop the best methods possible for clinical trials. This will help to make sure that research studies are relevant and correctly measuring what we want to measure. The Hub also works in collaboration with patients and service users to make sure their experiences of clinical trials and health conditions are included in developing better methods for carrying out clinical trials. Together we are committed to making sure that the best methods possible to design, run and analyse clinical trials are researched, developed, used and further evaluated. The Hub focuses on four themes: - Early phase trial design and analysis, (when drugs are first researched to check for their safety and to see what effect they have) - Later phase trial design and analysis and (when drugs are checked to see how well they work in routine care) - Patients' perspectives, (what patients' experiences of taking part in clinical trials are) - Efficacy and mechanism evaluation of targeted therapies (choosing the right drug or drug dose to give to a patient, sometimes referred to as 'personalised medicine') We want to make sure that we develop good methods that can be used in key clinical areas and we have a particular interest in drug safety, medicines for children, mental health, epilepsy, cancer, surgical trials and infection. The major aims of the Hub are to: - Provide a world-class environment for carrying out research that will improve the design, conduct and analysis of clinical trials; - Make sure that our findings are used to improve the methods used in future clinical trials. - Set up training programmes to develop the next generation of clinical trial experts. - Work in partnership with others, both in the public sector and industry. The key objectives are to: - Improve the design, conduct, analysis and reporting of clinical trials; - Develop a methodological research portfolio generated by a broad team of investigators from a range of disciplines; - Build on considerable local Cochrane expertise to improve the integration between trials and systematic reviews in relation to trial design and reporting; - Use local strengths in pharmacology (the study of drugs) to improve the design of drug clinical trials; - Train the next generation of clinical trials experts; - Work well with industry in developing good clinical trials; - Publicise the work that we have done. Key achievements to date include: - The COMET (Core Outcome Measures in Effectiveness Trials) Initiative (www.comet-initiative.org) - this project works with international experts and patients interested in the development and application of agreed standardised sets of outcomes, known as 'core outcome sets'. - The Database of Instruments for Resource Use Measurement (DIRUM www.dirum.org), (A bank of tested questionnaires for use by health economists) - A network meeting "Improving accrual and recruitment conduct in clinical trials with children and other patients unable to consent for themselves" (http://www.liv.ac.uk/nwhtmr/events/past_events/recruit_meeting.htm. Further details are available at http://www.liv.ac.uk/nwhtmr.