NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Changing behaviours towards single-use textiles in the operating theatre
Funder: Medical Research Council

Abstract: The carbon footprint of the NHS is 4.4% of the total of the UK, and the supply chain accounts for 62% of this.  Reuse of medical equipment has been identified as a priority area for carbon reduction.  In the UK the market for operating theatre textiles - theatre gowns (worn by the surgical team) and drapes (used to cover the patient and operation site) is dominated by single-use textiles. >60% of gowns and >75% of drapes in the UK are currently single-use.  Yet reusable textiles are preferable in almost all important aspects.  Over their life-cycle, reusable textiles have 2-3 fold lower carbon than disposable equivalents. They have 4 to 10 fold higher tensile strength, 10 fold lower burst susceptibility and 8 fold lower linting. They have better breathability, aiding temperature regulation for staff and patient. They have lower lifetime financial cost.  Over 94 million single use gowns and drapes are purchased each year by the NHS in England, and switching these to reusables could save 66 thousand tonnes of carbon dioxide.  We will undertake a 12 month "action-based" body of work that will educate and inform decision makers, to help engender a system where reusable textiles become the norm in the NHS.  Through interviews with key informants, we will first investigate the potential manifold reasons for continued preference of single use textiles in hospital settings.  Informed by those findings we will create a short professional animation to educate and inform, targeted at those involved in decisions about procurement and use of textiles in the operating theatre.  We will maximise impact of our intervention by distribution through our exceptional and established network of national and international partners of representative medical bodies in the fields of surgery and healthcare.


Research Activity Codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Characterisation of a novel GBA-L444P BAC transgenic mouse model of Parkinson’s disease.
Funder: Wellcome Trust

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, currently affecting 145,000 people in the UK. It is known that specific mutations in certain genes can increase the risk of developing Parkinson’s disease. One such gene is GBA, which represents the greatest genetic risk factor for developing PD. Despite this, we still don't fully understand how mutations in GBA increase the risk of developing PD and progress is limited by the lack of relevant animal models of GBA-associated PD. The Wade-Martins lab has therefore developed a new mouse model to study GBA-associated PD. These mice harbour a human GBA gene, which contains a mutation called L444P. My project will use biochemical, electrophysiological and behavioural techniques to investigate how disease in these mice progresses with age. I will also assess the effectiveness of potential therapeutic strategies at restoring the function of GBA. The second phase of my project will characterise pathology in stem cell derived dopaminergic neurons from Parkinson’s patients. These neurons also carry the L444P mutation in GBA, which will allow the translation of pathological findings in the mice into human neurons. This project will contribute to the field’s understanding of the pathology of GBA-associated PD.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure
Funder: Medical Research Council

Abstract: Liver failure is associated with increased susceptibility to infection which leads to multi-organ failure and increased mortality (1,2) . In an animal model of liver failure, innate immune system defects in monocyte/macrophage phagocytic function allowed circulating micro-organisms to disseminate and initiate sepsis (3). Blockade of the immunoregulatory molecule PD-1 restored phagocytosis in a rodent model of acute liver injury and in monocytes from patients with acute liver failure (4).  To determine whether PD-1 blockade exerts the desired therapeutic effect in-vivo we will treat patients with acute liver failure (N = 21) or acute decompensation of cirrhosis (N = 51) with the anti-PD-1 antibody, Nivolumab. Monocyte phenotype and phagocytic function will be measured ex-vivo using flow cytometry techniques and differences before and after treatment used to determine whether normal immune function is restored.  Safety of anti-PD-1 therapy will be explored in a sentinel cohort of patients treated with a 50% dose of Nivolumab and followed for 6 months. The incidence of infection will be carefully documented in patients with acute decompensation and compared to the expected incidence (35%) to determine whether anti-PD-1 treatment exerts the desired effect on infection rates.  Macrophage PD-1 expression was associated with the level of soluble PD-L1 (sPD-L1) in plasma (4). We will therefore measure sPD-L1 in cohorts of patients with acute liver failure or acute decompensation to determine whether this biomarker will predict patients at enhanced risk of sepsis in order to potentially target anti-PD-1 therapy


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Checkpoint control of T cell-B cell collaboration in the regulation of autoimmunity
Funder: Wellcome Trust

Abstract: Productive communication between T cells and B cells is vital for protective immunity, however dysregulation of this process can trigger autoimmunity.  Costimulatory checkpoints limit T cell help for B cells by controlling the differentiation of follicular helper T cells (Tfh), a cellular subset overrepresented in multiple autoimmune diseases. We have found that anti-CTLA-4 antibodies can trigger spontaneous Tfh differentiation in mice. Targeting CTLA-4 with checkpoint inhibitors in cancer patients may therefore induce Tfh, potentially relevant to the autoimmune side-effects seen with these treatments. Despite their escalating clinical burden, the cellular mechanisms underpinning checkpoint-inhibitor induced autoimmunity remain poorly understood.
 
In this proposal I will investigate the hypothesis that induction of Tfh responses is a general feature of autoimmunity, reflecting a loss of costimulatory (checkpoint) control. I will explore how CTLA-4 and PD-1 co-operate to regulate Tfh differentiation, and establish the consequence of a Tfh response for tissue autoimmunity. Insights will be drawn from autoimmune patients treated with CTLA-4-Ig, and cancer patients treated with CTLA-4 antibodies. Building on exciting preliminary data, I will determine whether Tfh populations have value in predicting outcomes in classical autoimmunity as well as in checkpoint-inhibitor induced disease.

Lay Abstract: Immune cells called T cells and B cells need to work together in harmony to generate effective immune response to clear infection. However if this cellular dialogue is dysregulated, the immune system can attack our own bodies, leading to autoimmune diseases like type 1 diabetes, rheumatoid arthritis and lupus. A particular subset of T cells specialises at communicating with B cells, and these T cells are increased in people with autoimmune diseases. The new drugs we use to fight cancer can cause autoimmune side-effects, and we have found this same type of T cell is increased in response to these drugs. We therefore want to understand how the development of these T cells is controlled and how they contribute to either natural or drug-induced autoimmune disease. Our work may lead to these cells being used as a marker to predict development of these diseases permitting them to be treated earlier.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Award Title: Chemistry in Cells – New Technologies to Probe Complex Biology and Medicine.
Funder: Wellcome Trust

Abstract: This Programme will provide unique training for a new generation of scientists focusing on the quantification of biologically-important molecular interactions in physiologically-relevant settings. It is currently impossible to accurately and directly quantify interactions of molecules, and their consequences, in the complex physiological settings relevant to diagnosis and treatment of disease. To address this unmet need, we will harness physical science-based approaches to develop technologies that will underpin research across the spectrum of cell biology and biomedical science  Scientific goals:     • Collaborative research outputs (papers, patents) using innovative approaches to provide new insights into biomedicine.   • Adoption of our technologies by the broad biomedical research community to study fundamental biology/diseases including Alzheimer’s, schizophrenia and cancer.    We have developed an innovative framework for our training programme, promoting a diverse and positive research culture change that we aim to propagate across Oxford and the UK.  Culture-change goals:     • Promotion of a positive research culture in Oxford demonstrated by uptake of our practices across the University.   • Communication of our strategies via lectures on graduate education and publications in educational journals.     These ambitious goals provide an exceptional basis for a multidisciplinary programme that trains scientist equipped as problem solvers for a diverse range of 21stcentury workplaces.


Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Award Title: Children’s developing understanding of others’ minds across intergroup divides
Funder: The British Academy

Abstract: The ability to make inferences about the mental states of other people is important for effective and harmonious social interactions. Research has historically focused on investigating the cognitive precursors, trajectory and correlates of this skill in childhood. This project will bridge research areas in developmental and social psychology in a novel line of inquiry to ask whether children are selective in their reasoning about the mental states of others, specifically in intergroup contexts. Experiment 1 will manipulate and test the effect of intergroup competition on children’s mental state inferences using novel groups. Experiment 2 will situate this research question in a society that is historically characterised by intergroup divides and competition - Northern Ireland. The results have the potential to substantially alter the study of children’s mental state understanding to account for the role of socio-cultural processes, and contribute to theories on the origins of intergroup bias.


Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: MENTAL HEALTH
Award Title: Chromatin and Development
Funder: Medical Research Council

Abstract: Our long-term goal is to understand the transcriptional and epigenetic events that underlie the process of mammalian development. In particular, we focus on the parts of the genome made up of transposable elements (TEs): elements known to be historically or currently mobile within our DNA. Significantly less is known about TEs compared to single copy protein-coding genes despite their high abundance in the human genome. This includes during mammalian development, where the role of relaxed TE repression and increased TE expression is not understood. Our previous work has revealed that the TE, LINE1 plays essential functions in controlling gene regulatory networks in the earliest stages of pre-implantation development (Percharde et al., 2018). This is interestingly independent of retrotransposition activity, and distinct from somatic cells, where increased LINE1 expression has been associated with cancer, inflammation, or senescence. These findings highlight how much is still to be learned about TE function in multiple contexts. Our objectives are firstly to investigate how TE expression and regulation has been co-opted for essential processes in mouse and human developmental contexts. Second, we aim to compare and contrast TE regulation in developmental versus disease states to understand how TE mis-regulation occurs and how this contributes to disease. We use a combination of mouse and human somatic and embryonic stem cell lines together with mouse embryo models to explore mechanisms regulating TE expression. Our experimental approach combines both candidate and genome-wide techniques, bioinformatics and CRISPR technology to uncover new TE regulators as well as to directly manipulate TE expression. Overall, we aim to shed light on how TE expression contributes to normal embryo development and uncover mechanisms to explain how and why these elements may contribute to disease.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Chromatin structure and mobile DNA
Funder: The Francis Crick Institute

Abstract: The early phase of the retroviral replication cycle begins with the viral entry via fusion of viral and cellular membranes and culminates with irreversible integration of the viral genetic material into host cell genome. Research in our laboratory focuses on HIV DNA nuclear import, integration and cellular innate defence factors counteracting viral entry. Using X-ray crystallography and cryo-electron microscopy we aim to elucidate molecular mechanisms underlying in these processes. The catalytic events associated with integration are catalysed by an essential viral enzyme, which is structurally and mechanistically related bacterial and eukaryotic transposases. Members of this superfamily are distinguished by the characteristic structural fold, organization of the active site and metal-dependent catalysis. Retroviral integrase acts in the context of a stable synaptic complex, known as the intasome. The latter is the target for integrase strand transfer inhibitors, the only class of HIV integrase antagonists currently approved to treat HIV/AIDS. Over the recent years, using a range of model systems, we determined a collection of high-resolution intasome structures, which explained and illustrated the mechanism of the retroviral integration process. Our structures also revealed the general mode of action of the clinical HIV integrase inhibitors.  The brunt of our current efforts is directed towards understanding the structural features specific to HIV/lentiviral integrase and the rules of engagement between the HIV integration machinery and the cellular environment. The two major projects aim to elucidate the structural and functional features of the interface between integrase and chromatin and the identification and the roles of host cell factors during integration. An example of our recent work related to HIV nuclear entry is the series of crystal structures of Transportin 3, the -karyopherin involved in the early steps of HIV replication in addition to its role in nuclear import of cellular Ser/Arg-rich splicing factors. We are currently investigating how Transportin 3 interacts with another important host factor CPSF6. The work related to viral entry currently focusses on the SERINC family of conserved multi-pass transmembrane proteins implicated in restriction of retroviral infection and on the mechanism of viral escape from the control by the cellular defence factors. High resolution structural information obtained in the course of our studies will be of considerable value for antiviral drug development. In particular, we are collaborating with medicinal chemists, whose efforts to develop next-generation HIV integrase inhibitors are informed by our retroviral intasome structures.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: CANCER AND NEOPLASMS;INFECTION
Award Title: Chronic hyperglycaemia and impaired pancreatic beta-cell function.
Funder: Medical Research Council

Abstract: Diabetes is a global health problem primarily caused by the inability of pancreatic beta-cells to secrete adequate levels of insulin. However, the molecular mechanisms underlying the progressive failure of beta-cells to response to glucose in type-2 diabetes remain unresolved.  Preliminary data reveal that diabetes produces marked impairment of oxidative metabolism and ATP synthesis in islets and beta-cells exposed to diabetes or chronic hyperglycaemia. As a result, insulin secretion is abrogated. The aim of this proposal is to elucidate the molecular mechanisms by which chronic hyperglycaemia impairs beta-cell metabolism. We will (i) determine where the metabolic block occurs and if it can be bypassed by downstream metabolites; (ii) determine if glucose or a metabolite mediates the effects of chronic hyperglycaemia, and identify the key metabolite(s) involved; (iii) investigate if the glucose-induced changes are mediated by reciprocal changes in mTORC1 and AMPK activity, as preliminary data suggest; (iv) determine how high and for how long glucose must be elevated to cause these effects; and (v) explore if reducing metabolic flux can prevent the changes in gene expression and beta-cell metabolism produced by chronic hyperglycaemia. As substantial amounts of glycogen accumulate in diabetic beta-cells, we will also investigate if this is a cause or consequence of the impaired metabolism. Finally, we will determine the extent to which the effects of chronic hyperglycaemia on beta-cell metabolism and insulin secretion can be reversed by: (i) restoration of euglycaemia, both in vivo and in vitro; and (ii) drugs such as metformin.  Improved understanding of the proteins and pathways involved in the deleterious effects of chronic hyperglycaemia on beta-cell metabolism is expected to identify new targets for the development of therapeutic drugs designed to preserve beta-cell function and improve insulin secretion in diabetes.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Circuit Mechanisms of Learning and Decision Making
Funder: Wellcome Trust

Abstract: Decision making concerns every aspect of our lives. Despite substantial progress in understanding the brain regions involved in learning and decision making, the neuronal circuits that govern choice behaviour have remained elusive. This proposal aims at studying precise neuronal circuits underlying learning and decision making. We will focus on frontostriatal neuronal circuits, and how neuromodulators can shape the activity of these circuits during decision making. Our research will take the following complementary directions: A) We will examine defined frontostriatal circuits during a novel decision paradigm that requires integration of perceptual and reward signals in order to investigate the role distinct frontostriatal circuits play in choice behaviour. B) We will focus on dopamine neurons and dopamine recipient structures and examine specialised roles of distinct dopaminergic circuits in learning. C) We will establish how decision uncertainty influences learning, and how dopaminergic circuits regulate learning in uncertain environments. Our group will utilize and develop behavioural, computational, large-scale electrophysiological and imaging tools to study genetically- and anatomically-defined neuronal circuits in behaving mice. These studies will result in a quantitative circuit-level understanding of complex choice behaviour, and will ultimately provide insights into the pathophysiology of diseases compromising cognition.

Lay Abstract: Decision making concerns every aspect of our lives. Research in neuroscience has identified brain regions which play fundamental roles in choice behaviour. However, it remains unknown how the neuronal circuits embedded in these brain regions regulate learning and decision making. Our team aims to answer this question at the level of individual neurons and the communication pathways among them. We will teach mice to perform a simple decision task. Meanwhile, we will study the electrical activity of cells in the front part of the brain, a critical node for decision making, and dopamine-producing cells, known to be involved in learning. We will go one step further and test if we can influence learning by activating specific cellular communication pathways using novel optical methods. By understanding the cellular foundation of decision making, this research could shed light on why and how the brain begins to dysfunction­ in psychiatric disorders.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: City of London AZ-CRUK Clinical Academic Training Award
Funder: Cancer Research UK

Abstract: The CoL Centre is ideally placed to train and support AZ CRUK CRTFs; as a world class hub in cancer biotherapeutics the Centre’s unique partnerships bring together a wealth of resources in terms of infrastructure, technical expertise, knowledge, networking, collaborations and access to training. The strategic priorities of AZ and CRUK run parallel with the CoL Centre’s research objectives, thus the Centre is ideally placed to host these fellows.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Clinical Development and Validation of a Novel Optical Facebow based on Deep Learning
Funder: Innovate UK

Abstract: Digital dentistry is the future. Dental patients and dental professionals alike increasingly expect better, more predictable and cost-efficient outcomes for their treatment and incorporating the latest technology is a logical step in achieving those aims.



CAD/CAM and the use of 3d scanning and printing is in common use in many industries, but many dentists and dental technicians have been relatively slow to fully adopt this digital approach.



The barriers to adoption entry are: in the main, high cost, poor accuracy of the scanning technology and limitations of use for certain more complex, but common dental procedures.



3d scanners, which scan impressions or models of a patient's teeth, are in use in both dental surgeries and dental laboratories and. They can simplify the process of creating dental crowns, bridges, implants and dentures., hHowever, it is a common problem too often thethat scans taken of what is a highly complicated anatomical structure are insufficientlynot accurate enough to work from and consequently result in poor fitting dental work which may lead to failure or future complications. Critically, the inability to accurately record the patient's jaw relationship and relate that to key facial landmarks digitally means that much digital technology has limited applications in more advanced restorative dentistry reconstruction and smile design treatment planning.



Overcoming these problems will improve patient experiences, dental health and make a complicated clinical process much more efficientstreamlined.



By undertaking this project, Mimetrik Solutions Ltd, a spin-out company incorporated to commercialise the research and development output of the Digital Dentistry Department of the School of Dentistry at the University of Leeds, will seek to solve the issues commonly seen in all the 3d scanning equipment currently available in the marketplace. Building on over ten years' work by world- leading experts in the field, an advanced prototype that has already been tested and validated in a large multi-centre pilot study will be developed further to ensure the device is ready for commercial manufacture so that the benefits it can bring can be accessed by all.


Research Activity Codes: 5.3 MEDICAL DEVICES
Health Categories: ORAL AND GASTROINTESTINAL