NIHRDataInsights/HRCSData huggingface dataset:
Title: MICA: Psoriasis Stratification to Optimise Relevant Therapy (PSORT)
Funder: Medical Research Council

Abstract: Biologic therapies for severe psoriasis are currently prescribed in a stochastic manner that is neither efficient nor cost-effective. The vision of the PSORT consortium is to better understand determinants of response to biologic therapies and deliver, in close collaboration with commercial partners, a PSORT stratifier (algorithm) to guide psoriasis management. This will optimise clinical pathways for psoriasis, inform the management of other less accessible immune-mediated inflammatory diseases and deliver health care savings. To deliver this vision PSORT has brought together a powerful grouping of world-leading psoriasis researchers, bioinformaticians, statisticians, health economists and industry partners. Patient representation informs the consortium which utilises NIHR and MRC funded platforms and an established, high-quality clinical bioresource the British Association of Dermatologists' Biologic Interventions Registry (BADBIR) involving 143 UK dermatology centres (5500 patients by 2014). Two parallel, interlinked Work Strands will provide clinical, adherence, pharmacological, genetic, transcriptomic, and immune data in blood and skin on psoriasis patients treated with biologics. Deeply-phenotyped Discovery and Refinement cohorts sponsored by academia and industry are complemented by large scale validation in BADBIR and in a prospective clinical pilot study of minimal effective dosing of biologics. The data will be integrated and interrogated through TranSMART infrastructure enabling a combination of bioinformatics, machine learning and biostatistics for the discovery of drug response endotypes/biomarkers. Working with our partner diagnostics companies these will be scalable for clinical use. Operational management will be proactive and milestone driven with oversight provided by an Independent Advisory Board. It is anticipated that the PSORT consortium will be a major catalyst to deliver novel personalised medicine approaches in the management of psoriasis.


Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: SKIN
Title: DNA hydroxymethylation, TET enzymes and regulation of stem cell activity during skin regeneration and wound healing
Funder: Medical Research Council

Abstract: Epigenetic mechanisms play an important role in the control of stem cell activity during development and regeneration and understanding how and why these mechanisms are altered in many disorders (cancer, autoimmunity, impaired wound healing, etc.) has become a growing priority in biomedical research. The long-term goals of this collaborative project are to understand the mechanisms that control the establishment of lineage-specific patterns of gene expression and chromatin organisation in adult stem cells during the process of differentiation into specialised cell types in normal and regenerating epithelia. TET1/2/3 enzymes are a group of recently discovered epigenetic regulators that promote oxidation of methylated DNA and conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). 5mC DNA oxidation is required for gene activation in mammals and plays an essential role in many biological processes including development, cell differentiation and cancer. Here, we will test the hypothesis that Tet1/2/3 proteins are critical determinants that control gene expression programmes in adult epithelial stem cells and their progenies during skin regeneration and wound healing via two Specific Aims: 1) Define the common features and differential impact of the distinct Tet proteins on the self-renewing and differentiation potentials of epithelial stem cells and their progenies during physiological hair cycle-dependent skin regeneration. 2) Identify the role of Tet proteins in the control of activity of skin epithelial stem cells and their lineage-committed progenies (epidermal keratinocytes) during wound healing. This project will provide new important insights into fundamental mechanisms that regulate stem cell activity inside and outside of the skin, and will serve as an important platform for the development of novel epigenetic drugs to target stem cells for the needs of regenerative medicine and stem cell-based therapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Defining the Biological Functions of Novel Lipids in Healthy and Wounded Skin
Funder: Medical Research Council

Abstract: Research objectives (Aims): (1) Determine structure and localization of LOX-derived lipids in human skin (healthy, eczema, psoriasis). Structural characterization (including enantiomeric) of the LOX-derived ceramides will be undertaken using Orbitrap mass spectrometry and chromatography. The localization of all LOX-derived lipids will be determined using MALDI mass spectrometry imaging and LC/MS/MS of human skin separated into distinct epithelial layers, using both healthy skin and samples from patients with inflammatory skin disorders (obtained through dermatology clinics at University Hospital Wales). (2) Determine regulation of barrier function, innate immune responses and wound healing in skin by LOX-derived lipids. A 3D cultured human skin system and in vivo murine model of wounding will be used. PPAR/TG activities will be tested using gene expression and immunohistochemistry analysis. Innate immune responses will be tested by flow cytometry analysis of migrating blood cells into skin, and determination of chemokine/cytokine levels using ELISAs. (3) Characterise regulation of skin gene expression by LOX-derived lipids. Skin LOXs will be downregulated in cultured human skin by delivery of siRNA using microneedles. RNAseq and network analysis will determine global changes in gene expression in specific skin compartments and transcription factor involvement. (4) Discover new lipids formed in skin disease. Using a new method (Orbitrap, LipidArray), the total number and diversity of lipids will be catalogued in biopsy samples of healthy skin, and from patients with the common skin disorders, psoriasis and eczema. Samples will be obtained from dermatology clinics at University Hospital Wales.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Kindlin and EGFR control convergent pathways to regulate epithelial cell function
Funder: Medical Research Council

Abstract: The goal of this project is to integrate the identification of new mutations in patients with skin blistering with a cell biological analysis of the defects in mammalian cells, and exploitation of the genetics of Drosophila to group components into novel pathways. Our serendipitous findings to date provide us with a unique opportunity to interrogate the co-operation and convergent molecular signatures of EGFR and kindlin-1-dependent skin disease. Our first goal is to confirm that Kindlin-1 regulation of EGFR is a key part of its unique function that cannot be substituted for by Kindlin-2. Second, we wish to identify the mechanism by which Kindlin-1 regulates EGFR levels. Third, we aim to identify the common mediators of targets of EGFR ad Kindlin-1 signalling that mediate the epithelial cell adhesion. These studies will characterise novel candidate genes and mechanisms that contribute to skin fragility disorders using a powerful combination of in vitro and in vivo models: human keratinocytes (from healthy volunteers and KS patients) and the genetically tractable organism Drosophila. We anticipate that the knowledge gained will improve our understanding of how changes in levels or activation of each of the pathway components gives rise to the disease pathology, suggests possible treatments, and aids in the identification of less serious skin conditions that may arise from a more mild impairment of these pathways.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: SKIN
Title: The development of topical Salbutamol to prevent human skin scarring and hyperpigmentation
Funder: Medical Research Council

Abstract: 110 million primary surgical incisions occur globally every year. Scars can cause serious cosmetic and functional problems. This is especially true for patients with darker skin tones who often suffer disfiguring hyperpigmentation. Scars place a heavy financial burden on healthcare systems worldwide. No clinically proven treatment is available to reduce wound fibrosis and scarring. Salbutamol (Sal) is a well-tolerated pharmaceutical, evidenced by its long-standing use for asthma treatment. Previous work by Pullar (12+ papers) details Sal-mediated mechanisms for modulating wound repair. The results from an MRC-funded "proof of concept" grant (G0901844) demonstrated that Sal altered physiological processes during healing, ultimately reducing scar area and hyperpigmentation by almost 50%, significantly improving scar appearance (Le Provost and Pullar, 2014). Two patent families (scar/hyperpigmentation reduction) are under examination in US and Europe. Sal and placebo gels will be formulated, stability tested (ICH GCP) and manufactured (GMP). A dose-ranging porcine study will be performed to determine the optimum dose for scar prevention. An MHRA suggested non-clinical porcine safety study will be conducted (GLP) to satisfy regulatory requirements for topical Sal registration. A within-volunteer, placebo controlled, double-blinded clinical trial will be conducted (GCP) in healthy volunteers to test Sal safety, tolerability and efficacy to prevent scarring in 2cm linear incisions, under each arm. Scars will be assessed at 6, 9 and 12 months post-wounding. The ultimate aim is to determine efficacy in patients. Potential Phase II populations are those undergoing cardiothoracic/ abdominal primary surgery. Sal, applied post-surgery, would be highly beneficial to the patient, surgeon and the NHS, reducing the subsequent need to treat scars and improving the patients' health and quality of life. Ultimately we plan to inform novel NICE guidelines on scar prevention


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: SKIN
Title: Dissecting the function of GORAB, the protein mutated in Geroderma osteodysplastica
Funder: Medical Research Council

Abstract: Geroderma osteodysplastica (GO) can be classified a progeroid disorder, with characteristic symptoms of loose, wrinkly skin (cutis laxa) and osteoporosis. GO is caused by mutation of GORAB, also called Scyl1BP1, a coiled-coil protein localised to the Golgi apparatus. The cellular function of GORAB is not known, and we do not know how its loss leads to the pathological changes observed in GO patients. In preliminary studies we have found novel interactions between GORAB and components of the COPI machinery that mediates intra-Golgi trafficking. We have also observed changes in protein glycosylation in GO patient cells, consistent with altered intra-Golgi trafficking of glycosylation enzymes. We therefore propose that GORAB functions in intra-Golgi trafficking of glycosylation enzymes, and that GO is a genetic disorder whose symptoms are attributable to defective glycosylation of extracellular matrix proteins comprising the skin and bone. We aim to investigate these hypotheses using a combination of biochemical and cell biological approaches using both cultured cell lines, including GO patients' dermal fibroblasts, and patient-derived skin biopsies. Together the findings will reveal the mechanistic basis for GO, and also inform us more generally of how COPI mediated trafficking and protein glycosylation are controlled. The work also has relevance to our understanding of ageing and tissue maintenance and repair, which are dependent upon proper generation and maintenance of the extracellular matrix.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Role of the Polycomb group gene Cbx4 in the control of skin regeneration and wound healing
Funder: Medical Research Council

Abstract: Epigenetic mechanisms play important roles in the control of stem cell (SCs) activity during development and regeneration, however understanding of how these mechanisms become altered as a result of disorders (cancer, impaired wound healing, etc.) is increasingly seen as a priority in biomedical research. The Polycomb group proteins are transcriptional repressors playing critically important roles in the control of stem cell activity and their differentiation into specialized cell types. By interacting with each other and forming multi-protein complexes, they mediate histone modifications leading to chromatin compaction and gene silencing. Here, we will test a hypothesis that Polycomb group gene Cbx4 is a critical determinant that controls maintenance of epithelial identity and the proliferative activity of the skin epithelial SCs during physiological and injury-induced skin regeneration via two Specific Aims: 1. Define the role for Cbx4 in the maintenance of proliferative activity, epithelial identity and differentiation of skin epithelial SCs during hair cycle-associated skin regeneration. 2. Identify the role of Cbx4 in balancing between epidermal commitment and epithelial-mesenhymal transition in epithelial SCs during wound healing. To address these aims, we will generate genetically modified mice with the deletion of Cbx4 in K14+ and K15+ skin epithelial SCs. In addition to mice, we will use ex vivo human skin wound and 3D organotypic models to assess the role of Cbx4 in human skin maintenance and regeneration. Together, this study will allow us to comprehensively analyse the consequences of Cbx4 loss in skin SCs for normal physiological and injury-induced regeneration. This project will provide new important insights into fundamental mechanisms that regulate SC activity inside and outside of the skin, and will serve as an important platform for the development of new epigenetic drugs to target stem cells for the needs of regenerative medicine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: TARGETING MIR-29 FUNCTION IN CUTANEOUS WOUND REPAIR
Funder: Medical Research Council

Abstract: A large percentage of the population suffers from impaired wound healing, and the incidence of chronic, non-healing skin ulcers is continuously increasing in an aging society. The development of efficient strategies for the improvement of wound repair requires understanding of the mechanisms underlying normal and impaired healing. Many factors can interfere with one or more phases of cutaneous healing process, thus causing improper or impaired wound healing in patients. Recent data implicates microRNAs (miRs) as one such factor involved in wound repair. Because of the short sequence (~20 nt) and the tissue-specific activity, miRs may be targets for oligonucleotide (ON)-based RNA silencing therapy. This approach is particularly promising in the skin due to the accessibility of this tissue that allows local miR manipulation. miR-29 regulates collagen production by fibroblasts and is a new therapeutic target in the Phase I clinical trial for cutaneous sclerosis. However, the regulation and functions of miR-29 in homeostatic and regenerating skin remain largely unknown. My previous work identified an important function of miR-29s in regulating desmosomes in normal and hyperproliferative epidermis. This proposal will build on these findings to determine keratinocyte-specific functions of miR-29s in normal epidermis and during re-epithelialization of cutaneous wounds. I will use miR crosslinking and immunoprecipitation (miR-CLIP) to identify mRNA targets of miR-29s in human keratinocytes. I will also use modified antisense miR-29 ON for efficient delivery, tracking, and downregulation of miR-29 function in murine wounds in vivo and in the wound model of the 3D cultures of human keratinocytes ex vivo. These experiments will identify new RNA targets of miR-29s that regulate growth and differentiation of human keratinocytes and will develop a novel oligonucleotide-based miR/RNA silencing approach to improve cutaneous wound healing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Dupilumab for treating adults with moderate to severe atopic dermatitis [ID1048]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of dupilumab within its marketing authorisation for treating adults with moderate to severe atopic dermatitis.

Lay abstract: Atopic dermatitis (also known as atopic eczema) is a long term condition that affects the skin. It is characterised by a red blotchy rash, dry, itchy and inflamed skin. The skin can also ooze and weep. Constant scratching can cause the skin to split and bleed, which can cause skin infections. Severe eczema can be physically disabling or incapacitating, and can cause anxiety or depression. Estimates of the prevalence of atopic dermatitis vary. It is more common in childhood (affecting 1 in 5 children in the UK) and affects 1 in 12 adults in the UK.(1) In 2014-15, there were 895 admissions, including 604 adults for atopic dermatitis in England (2) Atopic dermatitis is usually managed in primary care. Treatment strategies include advice on the avoidance of factors that can provoke dermatitis, such as soap, and the use of emollients to moisturise and relieve symptoms. For flares, or dermatitis that does not respond to these measures, topical corticosteroids are normally prescribed once or twice daily in conjunction with continued use of emollients (TA81). Tacrolimus ointment (calcineurin inhibitor) is recommended when moderate to severe atopic dermatitis has not been adequately controlled by use of topical steroids at the maximum strength and potency or where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy (TA82). Alitretinoin is recommended as a possible treatment for people with severe chronic hand dermatitis affecting their quality of life and not responding to potent topical corticosteroids (TA177). People with moderate or severe dermatitis not responding to topical treatments may be referred to secondary care and treated with stronger oral medications such as oral steroids, systemic immunosuppressants (azathioprine, ciclosporin, mycophenolate mofetil, and methotrexate). In addition, phototherapy and photochemotherapy (psoralen–ultraviolet A; PUVA) can be used to manage chronic severe atopic dermatitis.(3) References: 1 National Eczema Society. What is Eczema? Accessed November 2016. http://www.eczema.org/what-is-eczema 2 Health & Social Care Information Centre, Hospital Episode Statistics for England. Admitted Patient Care statistics, 2014-15. Accessed November 2016. http://content.digital.nhs.uk/catalogue/PUB19124 3 British Association of Dermatologists. Atopic Eczema. Accessed November 2016. http://www.bad.org.uk/shared/get-file.ashx?id=69&itemtype=document.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: SKIN
Title: Dermatology: Cutaneous Inflammation and Repair
Funder: Department of Health and Social Care

Abstract: Our objectives: Psoriasis  Short-term: Establish a novel care pathway with early, targeted implementation of lifestyle management and appropriate therapy;  Medium-term: Use biomarkers to predict response to traditional systemic therapies by identification of disease and drug response endotypes;  Long-term: Translate genomics, Langerhans’ cell and mast cell function findings in psoriasis into new targets for therapy and a proof-of-principle clinical trial. Photodermatoses  Short-term: Perform participatory research on sun-exposure behaviour to inform prevention in the photodermatoses;  Medium-term: Explore biomarkers predictive of cutaneous responses to sunlight and systemic therapies; perform proof-of-concept studies in personalised treatments for photodermatoses;  Long-term: Innovate further personalised strategies for photodermatoses. Inflammatory Hair Disease  Short-term: Identify candidate drugs that can restore human hair follicle (HF) immune privilege and/or protect HF epithelial stem cells from immunodestruction and/or epithelial-mesenchymal transition;  Medium-term: Probe candidate drugs for efficacy in lesional scalp skin organ culture to improve alopecia areata and lichen planopilaris;  Long-term: Run one clinical pilot trial for each disease using the top two candidate drugs identified. Wound Healing  Short-term: Identify indicators of healing in chronic wounds. Evaluate cutting-edge, non-invasive, diagnostic imaging tools for monitoring and quantitative evaluation of wound healing;  Medium-term: Evaluate prognostic power of endotypic factors in patient cohorts to discern modifiable indicators for therapeutic intervention;  Long-term: Evaluate targeted therapies for managing delayed wound healing in Phase I studies.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: SKIN
Title: BPSU study: The incidence, management and early outcome of congenital ichthyosis
Funder: Sparks

Abstract: Ichthyosis is a group of incurable genetic disorders characterised by thick, scaly skin. Of the subgroup known as “autosomal recessive congenital ichthyosis” (ARCI), harlequin ichthyosis (HI) is the most severe type, with rigid plaques restricting movement and breathing, blocking the ears and nose, and preventing closure of eyes and mouth. The plaques gradually shed leaving a disabling, disfiguring ichthyosis. Less extreme ARCI types present at birth with a collodion membrane (CM), where the skin is tight but less rigid. Almost half of babies with HI die in the first 2 months, most deaths occurring in the first 3 days. The incidence is unknown but there are at least 4 HI and 13 CM births per year in England and Wales. There is no evidence-based treatment and practice varies greatly: babies with CM may suffer unnecessary medical interventions, while some with the shocking appearance of HI are probably offered palliative care only, by staff unaware that this condition is treatable. There is no national expert service as there is for other rare diseases such as epidermolysis bullosa. We propose a prospective, population-based, observational cohort surveillance study of all babies born with HI and CM over two years in the UK, Ireland and Switzerland, conducted via the British Paediatric Surveillance Unit (BPSU https://www.rcpch.ac.uk/bpsu) who elicit monthly reports of selected diagnoses from paediatricians. We would send questionnaires to reporting doctors immediately and at 6 and 12 months. Our research objectives are to determine: Incidence of HI and CM, both live and still-births Variations in initial patient journey including whether and when transferred to neonatal intensive care unit (NICU) Variations in other maternal and fetal factors influencing outcome Variations in investigations and management Variations in outcomes including mortality and age at discharge. This information will inform the development of appropriate services in the future.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: SKIN