NIHRDataInsights/HRCSData huggingface dataset:
Title: Vulval Erosive Lichen Planus: Is systemic treatment better than topical alone for long-term disease control? Designing and performing a pilot multi-centre randomised controlled trial.
Funder: Department of Health (England)

Abstract: Erosive lichen planus affecting the vulva (ELPV) is a persistent painful condition that is hard to treat. There is no good evidence on which to base treatment. This project will involve patients and clinicians to design and subsequently run a pilot study in preparation for a full randomised controlled trial. The trial will aim to find the most effective and safe tablet treatment for patients with ELPV who haven't responded to creams or ointments. This project will add to existing knowledge, contribute towards the development of evidence-based treatment guidelines and help to improve the quality of life of patients with ELPV.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN
Title: Repairing the skin barrier in Junctional Epidermolysis Bullosa (JEB)
Funder: LifeArc

Abstract: Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth, caused by the loss of skin basement membrane proteins that anchor the outer layer of the skin to the rest of the body. The most severe form, JEB generalised severe, is caused by complete loss of one of the parts of laminin 332, which is a key component of the basement membrane. Babies diagnosed with this form of JEB do not survive beyond their first birthday. Current treatment for JEB is focused on palliative care, such as treating poor wound healing and infection, but this does not treat the underlying cause of disease. JEB patients therefore suffer from severe unmet need and require better, inexpensive treatments that can be made widely available and are more effective targeting disease mechanisms to improve on the treatment of disease symptoms. Dr Caley’s team had discovered a previously unreported characteristic of JEB skin, a loss of cholesterol from the skin of JEB patients. Within the skin, cholesterol plays an important role in maintaining the skin barrier preventing water loss, skin infection and dry skin-related itch. The team believes that the loss of skin cholesterol in JEB patients increases the severity of this disease. A restoration of skin cholesterol would not cure these patients but would improve their quality of life. The approach is to use QMUL’s simple model of JEB to identify drugs that can restore cholesterol in JEB, testing positive hits in more complex 3D JEB skin models and finally use a JEB mouse model to identify future treatments for JEB patients.The team aims to identify novel drugs for the treatment of JEB patients and validate them in preclinical models of the disease. Restoring cholesterol to the patient’s skin could improve both their quality of life and survival. The Epidermolysis Bullosa charity, DEBRA Austria, contributed €25,000 to the project.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN
Title: Ontogeny and function of human dermal dendritic cells.
Funder: Wellcome Trust

Abstract: Dendritic cells (DC) are critical inducers and regulators of the immune system. These cells coordinate appropriate immune responses to pathogens, vaccines and tumours. DC are bone marrow derived but located primarily in the peripheral tissues such as the skin, lung and gut. Owing to this, they are more difficult to study in humans than components of the immune system found in the blood, such as lymphocytes. Researchers have therefore previously used DC derived in vitro from other cells such a s blood monocytesl. My work aims to investigate how DC are generated in the body and what type of immune responses they trigger. In particular I want to determine the differences between DC in normal and inflamed skin and how human DC relate to DC in experimental models such as the mouse. I also aim to discover why there are different subsets of DC in both humans and mice and investigate the existence of a new DC precursor of one DC subset. Finally I will ask whether DC are ready-primed to ma ke responses to melanocytes (pigment cells) and whether this can be used to design protective treatments for melanoma, a common tumour of skin.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN
Title: Immune hypo-responsiveness caused by helminth infection of the skin; regulation of dermal antigen presenting cells.
Funder: Wellcome Trust

Abstract: Schistosomiasis is caused by parasitic worms that infect humans and animals through the skin. Infection can occur daily but little is known about how the immune system responds to repeated exposure. We have established an experimental model which reveals that the adaptive immune response is down-regulated and pathology to the egg is reduced. This project will establish which cell populations in the skin initiate the modulated immune response and determine the immunological components (e.g. cyt okines) involved. We suspect that a class of macrophages, (called alternatively-activated ), are central to effecting down-regulation as they are inefficient presenters of antigens but dendritic cells which are normally important in stimulating the immune system are also functionally non-responsive. Specifically, we will examine whether down-regulation is a response to tissue damage caused by invasive larvae, or specific recognition of parasite antigens. In tandem, we will determine the pro cess by which macrophages and dendritic cells differentially process parasite antigens in relation to their ability to present antigen to immune cells called T lymphocytes and stimulate effective immune responses. The project will reveal critical mechanisms of the dermal immune response, including how to turn off adverse inflammation which are relevant to combating autoimmune and allergic conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN
Title: Infection, Immunology and Translational Medicine - 'The role of novel members of the IL-1 family in psoriasis'
Funder: Wellcome Trust

Abstract: The IL-1 family cytokines IL-33 and IL-36s are increased in inflammatory skin disease but little is known about their function. In this project we will perform a systematic analysis of the role of IL- 1 family members in inflammatory skin diseases. We will determine how they influence disease initiation and perpetuation. The study will focus on in vivo as well as in vitro evaluation of IL- 33, IL-36s and their receptors. Their role in innate lymphocytes and regulatory T cells will be assessed. We will use a murine model of skin inflammation to analyze the kinetics and expression profiles of pathways suggested to be involved in psoriasis. Furtherwe will perform functional studies in knock-out and reporter mouse strains. These findings


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN
Title: Visualising costimulation and check-point regulation of cutaneous immune responses
Funder: Wellcome Trust

Abstract: We aim to study cutaneous immune responses in order to gain insight into the role of immune checkpoint mechanisms mediated by PD-1 and others in the steady state and inflammation. Questions of immune checkpoint roles in cutaneous regulatory T-Cell activities will also be interrogated. The effects of immune checkpoint inhibition will be examined in this context. There will be a focus on examining the dynamics of such responses via intravital microscopy to visualise migration, motility and real-time cellular responses in terms of activation and cytokine output. Models of cutaneous pathology, including components of infection, autoimmunity, allergy and cancer will be used with the goal of providing more physiologically relevant responses and antigen targets. We hypothesise that absence of PD-1 negative regulation on effector T-Cells will exacerbate inflammatory skin models and that the degree of tolerability in perturbing this system is related to PD-1 expression on regulatory T-Cells. We also aim to shed light on situations in which PD-1 is a dominant regulator and gain insight into effects on specific effector mechanisms (such as cytokine output).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN
Title: Cutaneous medicine
Funder: Department of Health and Social Care

Abstract: Aims  develop novel precision therapeutic strategies delivered through Cluster 1 for genetic, inflammatory, and neoplastic skin diseases;  develop biomarkers and co-diagnostics for genetic, inflammatory and neoplastic skin diseases;  deliver an internationally leading bioresource for the study of skin disease and outcomes with associated data collecting and warehousing tools. Objectives Short term:  complete phase I/II clinical trial of intravenous allogenic mesenchymal stromal cells in adults with recessive dystrophic epidermolysis bullosa (RDEB);  complete first-in-man cancer clinical trial using an in-house developed moAb (MOv18 trial – CRUK);  dissect immune responses in patients with melanoma, focusing on tumour-associated and tumour-induced B cells / antibody immune polarisation;  identify potential markers of disease and outcome in psoriasis and acne using genomic and immunological approaches;  roll out an in-house developed web based NHS firewall data capture tool (CAPTURE). Medium term:  complete phase I/II clinical trial of gene-supplemented autologous fibroblast intradermal injections in adults with RDEB (COL7A1 gene, SIN-lentiviral vector);  initiate phase II clinical study of MOv18 moAb;  prospectively validate molecular and immune stratification approaches in inflammatory skin disease;  discover monoclonal antibodies with novel anti-tumour properties and evaluate their anti-tumour efficacy and mechanisms of action;  functionally annotate genetic signals in psoriasis and acne. Long term:  develop gene-editing technologies for epidermolysis bullosa;  start clinical testing of a second in-house developed moAb targeting melanoma (CSPG4 moAb);  validate next generation integrated molecular and immune stratification tools for psoriasis and acne.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN;CANCER AND NEOPLASMS
Title: The role of the extracellular matrix in the initiation and resolution of psoriasis-like skin inflammation
Funder: Wellcome Trust

Abstract: Psoriasis is a skin disease associated with painful itchy lesions caused by immune cells entering the skin from the blood. Reoccurring flares of psoriasis often occur in the exact same patches of skin, suggesting these areas are primed for inflammation and never fully resolve. The components of the blood vessel wall regulate the migration of immune cells into skin and can be split into different layers. The glycocalyx is a layer of sugars and proteins lining the internal surface of the blood vessel wall, whilst the basement membrane is a layer of proteins covering the outside of blood vessels. Both layers can limit immune cell migration and are altered in inflammatory conditions. Despite the importance of immune cell migration to psoriasis, the role of these blood vessel components has not been fully investigated. We hypothesize that in psoriasis, blood vessel layers are changed to allow immune cell migration, but these changes are not fully reversed in resolved skin, allowing psoriasis to reoccur in the same location. This project will examine the make-up of these blood vessel layers in healthy, psoriasis and resolved psoriasis skin and will determine the significance of these changes to immune cell recruitment and inflammation in psoriasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;SKIN;CARDIOVASCULAR
Title: Understanding and manipulating innate-like B cell mechanisms to prevent stroke-associated infection
Funder: Medical Research Council

Abstract: Stroke-associated infection (SAI) is the most common complication of stroke, affecting up to one third of patients, and is independently associated with poorer short- and long-term outcome. Most infections occur early after stroke (50% within 2 d of onset) and bacterial pneumonia is the single most important cause of SAI. Currently, there are no effective treatments to prevent SAI and improve stroke outcome. Growing evidence suggests stroke-induced impairments in systemic anti-microbial immune function as a contributing factor to the high risk of infection in stroke patients. Our recent data have shown for the first time the potential importance to SAI of compromised systemic innate-like B cell immunity induced by stroke. We found that experimental stroke in mice induced rapid loss of splenic marginal zone B cells, impaired MZ antigen capture and suppressed circulating IgM levels. A similar IgM suppression was observed in stroke patients. Innate-like B cells comprise several subsets of B cells with molecular and functional characteristics of innate immune cells. They respond rapidly to infection and are particularly important for defence against opportunistic bacteria that cause pneumonia, in part through production of polyreactive IgM. Deficits in innate-like B cell function could be a particularly relevant mechanism in susceptibility to SAI. In this project, our objectives are to take our previous work further to identify the scale of stroke-induced innate-like B cell changes, define mechanisms and consequences of these changes and, in a proof-of-concept experimental approach, test if targeting anti-microbial function regulated by innate-like B cells can reduce susceptibility to SAI. We expect this work will show the translational potential for targeting innate-like B cell-directed mechanisms to prevent SAI in patients. Ultimately, we aim to use this work as a platform to progress to future trials in humans.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;STROKE
Title: Does stroke impair immunological memory and increase infectious disease risk during the chronic phase of recovery
Funder: Wellcome Trust

Abstract: Stroke patients are increasingly surviving long-term after the primary neurological insult. Post-stroke complications have thus rapidly become an area of unmet clinical need. Infection is a common and dangerous complication of stroke associated with increased death and disability. Stroke-induced immune suppression is associated with infection susceptibility, but the majority of studies have focused on short-term (hours to days) changes to immune function. My recent data show early reduced numbers of lymphocytes and dendritic cells in experimental and clinical settings. It is unknown whether this impacts adaptive immune function and immunological memory. Using experimental animal models and parallel analysis of population health data sets, key goals of this proposal are: 1. To understand the extent and persistence of changes to adaptive immune cells after stroke and how this relates to infection susceptibility. 2. To determine if previously generated adaptive immunological memory is lost after stroke. 3. To determine if generation of new adaptive immunological memory is impaired after stroke. This will generate understanding of the extent of adaptive immune memory deficits after stroke and the window of susceptibility in which stroke patients are vulnerable to infection and could result in new therapeutic approaches to reduce infection and improve long-term patient outcome.

Lay abstract: Increasing numbers of patients are surviving long-term after stroke. However, complications experienced during recovery can increase death, disability and worsen brain function. Infection is the most frequent complication of stroke but it is uncertain why patients have increased risk. We know that stroke causes some functions of the immune system, that normally protect us from infection, to stop working. Our adaptive immune system makes specific, protective immune responses against any possible infection. It also generates memory allowing more efficient immune responses on second exposure. My work has shown that immune cells important for immunological memory, are reduced in number after stroke. The overall aim of my project is to understand the scale of disruption to immune memory after stroke, and whether this increases infection risk, using experimental animal models and health data from patients. This may provide promising new strategies to reduce infection, disability and death during stroke recovery.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;STROKE
Title: The Feasability of Manufacturing Titanium Alloy Intramedullary Nails Economically with Enhanced Design Freedom (I-NEED)
Funder: Innovate UK

Abstract: The objective of this 1yr feasibility project is to address a clinical need to heal bone fractures more effectively and at lower cost. The project will involve the application of additive manufacturing, sometimes referred to as 3D-printing. The design & manufacture of tall, thin, Ti-64 intramedullary nails for repairing bone fractures will be addressed to enable them to be mass produced. Moreover, it is intended that the parts will be designed to suit specific types of bone fractures so as to enhance recovery. This development will particularly benefit the different bone injury requirements of younger active patients and the growing demands from the older section of the population. The project consortium will be led by CRDM with UCL Institute of Orthopaedic Medicine as its partner. Collaboration with a global medical device company, Smith & Nephew, will ensure that the technology is exploited through their UK orthopaedics sales channel.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: INJURIES AND ACCIDENTS
Title: Novel delivery mechanisms for the application of autologous keratinocytes to reduce scarring and wound contraction in children with scald and burn injuries
Funder: SPARKS

Abstract: In the UK almost 5,000 children per year are admitted to hospital with burns, most of them being under 5 years old. Scars caused by burns result in severe pain and difficulty in moving affected joints due to skin contraction. Children with scars often find difficulty in integrating socially due to changes in their appearance. This project seeks to improve survival and reduce scarring in children suffering from burn and scald injuries. Our previous work funded by Sparks has shown in an animal model that skin cells can be grown on microscopic beads in the laboratory and returned to the wound bed where they form new skin and reduce scarring. We now aim to undertake a clinical evaluation of the use of cultured skin cells to treat childhood burns, which has yet to be properly assessed or quantified. Skin colour, scar contraction and skin smoothness will be measured and compared in order to assess the effectiveness of this technique. Secondly, we will undertake a pre-clinical assessment of the efficacy of microcarriers to deliver skin cells to patients. The results from these studies will allow us to begin treating children with burns and scalds with microcarriers.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INJURIES AND ACCIDENTS
Title: Cross education of movement function across the lifespan
Funder: Biotechnology and Biological Sciences Research Council

Abstract: A significant risk associated with the fractures that arise from falls by older adults, is that the loss of specific muscle strength or general capacity resulting from limb immobilisation will leave the person below the level of capability necessary to perform everyday tasks, and thus maintain independent living. The phenomenon of cross-education, whereby practice with one arm enhances subsequent performance with the other arm has led to the supposition that the effects of disuse may be counteracted by training movements of the non-affected limb performed during the period of immobilisation. Although the phenomenon has been studied for more than a century, there is little consensus in relation to the neural mechanisms that mediate its effects. Two major theoretical models can be delineated: the 'cross-activation' model and the 'bilateral access' model. In order to provide a direct comparison of the explanatory power of these models, it is necessary to examine in the context of single tasks the relative impact upon cross-education of variations in the complexity of training movements, and the level of neural drive required for their execution. This unique approach is taken in the current project. In addition to theoretical considerations, a comprehensive understanding of the principles governing cross-education is required to ensure the optimum design of training programs that have as their aim the maintenance of functional capacity in older persons during limb immobilisation. Additional key objectives of the research are therefore to: establish the degree to which the balance that exists between factors that govern levels of cross-education varies across the lifespan; investigate the neural mechanisms that mediate their age-dependent influence; and assess age-related changes in the functional generalisation of cross-education to other movement tasks.


Research activity codes: 5.7 PHYSICAL
Health categories: INJURIES AND ACCIDENTS
Title: Disposable, low-cost test kit for arsenic in resource limited markets
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The effects of arsenic in drinking water have been called by WHO "The greatest mass poisoning of a population inhuman history" and whilst remediation is the long term solution the need for a quick, cheap, simple and accurate determination is immediate, to avoid poisoning, and necessary to prioritise and validate the remediation activities. In this project we intend to use the unique characteristics of an arsenite oxidising enzyme (specificity and catalytic activity) combined with the technology behind the glucose test strips used by millions of diabetics every day to produce a low cost and reliable arsenite biosensor suitable for field use in resource poor environments. The strips would give an accurate measure of arsenic levels at the 'well side' at a price point that will encourage widespread adoption.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INJURIES AND ACCIDENTS
Title: Do ACE inhibitors reduce postural instability in older people?: towards a novel approach to falls prevention
Funder: Chief Scientist Office (Scotland)

Abstract: Falls are a major cause of morbidity in older people. While a multifactorial approach is recommended, this is not always easily deliverable to all people at risk of falls. Moreover the effects of exercise therapy, the single most important intervention in the multifactorial approach, vy^ears away once it is stopped. Angiotensin Converting Enzyme Inhibitors (ACEi) may play a role in reducing falls through a range of mechanisms In a double blind placebo controlled, parallel group study, we will examine the effect of 15 weeks of the ACEi perindopril on postural stability as a phenotype at risk of falls in community dwelling older people. We will examine static postural stability, dynamic postural stability, muscle strength, magnetic femoral nerve stimulation to assess non-volitional muscle strength and fatigue. If our study shows positive results we will proceed to a large multicentre study of the effect of ACEi on falls as the primary outcome.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS