NIHRDataInsights/HRCSData huggingface dataset:
Title: MICA Therapeutic targeting of histone acetylation in scars
Funder: Medical Research Council

Abstract: Despite the ubiquitous nature and severe morbidity associated with scarring, there are no effective means to treat or prevent this problem. We recently found that histone deacetylase (HDAC)2 is significantly over-expressed in normal and keloid scars and suggest it may be viable therapeutic target. Evidence is increasing that HDAC inhibitors can indeed decrease fibrosis; however, it is not yet clear whether this is true for skin scars, or which HDAC family members, and which target proteins are responsible. Our first objective is to use genetic (over-expression/knock-down) and pharmacological approaches to manipulate HDAC2 in primary cultures of normal and keloid-derived dermal fibroblasts, and in this way define its contribution to cell proliferation, survival, differentiation and migration. The target proteins mediating the effects of HDAC2 in this context will also be explored. Next, to gain further insight into the importance of histone acetylation in scars, a second family of enzymes involved in its regulation will be studied. BET (bromodomain and extra-terminal domain) proteins (Brd2, 3, 4 and T) facilitate histone acetylation-mediated gene transcription, and we recently discovered that their inhibition in dermal fibroblasts inhibits proliferation and alters extracellular matrix gene expression. This led us to hypothesize that their inhibition may be of value in treating scars. The abundance and localization of Brd2, 3 and 4 will be analysed in: 1) primary human dermal fibroblast cells (normal and keloid, with or without TGFbeta1); 2) an in vivo model of wound-induced scar formation; and 3) normal and keloid human scar samples. Genetic and pharmacological approaches will again be used, this time to manipulate a BET protein in vitro, to define its contribution to scar-associated cellular changes. Finally, we will examine the value and feasibility of using an HDAC or BET inhibitor to counter wound-induced scarring by investigating the effects in an in vivo model.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Regulation of keratinocyte innate immune genes by psoriasis susceptibility alleles
Funder: Medical Research Council

Abstract: Aim Identify common, regulatory variants underlying psoriasis genetic association signals that affect the expression of innate immune genes in keratinocytes Objectives 1. Refine the localisation of disease associated signals containing innate immune genes 2. Determine the impact of candidate causal variants on keratinocyte gene expression Methodology 1.1 Association analysis of a dataset (6600 cases/15000 controls) of SNPs genotyped on the Immunochip. Loci containing innate immune genes will be analysed using software e.g. PLINK. Genotypes of additional SNPs will be derived using 1000 Genomes Project. Sample divergence (confounders) will be controlled using principal component analysis. Stepwise logistic regression conditioning on the most significant variant within each locus will be repeated to derive all signals reaching genome-wide significance. Risk variants will be functionally annotated using ENCODE and correlated with phenotypes. 2.1 To analyse the impact of candidate causal variants on transcription factor-DNA interactions, involved and uninvolved skin will be sampled from patients harbouring variants in the regulatory regions of innate immune genes. Each patient will be heterozygous for the regulatory variants. To ensure robust results, I will repeat the analysis of each variant in >3 patients. Chromatin immunoprecipitation-sequencing (ChIP-seq) will be performed using antibodies to transcription factors, as informed by bioinformatic analysis. Reads from sequenced ChIP products will be analysed using MACS. The effects of the susceptibility loci on gene expression will be determined by correlation with quantitative RNA sequencing from keratinocytes available in expression quantitative trait loci databases. Opportunities The research may lead to drug discovery, clinical trials and disease stratification. Given the overlap between autoimmune disease genetic determinants, cross-disciplinary medical and scientific opportunities will arise.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: MICA: The role of arginase in chronic delayed wound healing
Funder: Medical Research Council

Abstract: Chronic non-healing wounds lead to substantial morbidity and mortality imposing a major financial burden on health services. Current treatments are ineffective because the molecular and cellular correlates are poorly understood. Changes in L-arginine metabolism have been linked to tissue repair defects in multiple chronic degenerative diseases. Our data now show that a central L-arginine pathway component arginase (Arg1) plays a key role in skin wound repair, with inhibition or genetic ablation having a negative impact on healing outcome. Our data indicate widespread arginase expression in mouse and human skin cells (including keratinocytes, fibroblasts and macrophages). Surprisingly little is known about the contribution of non-macrophage arginase to pathological wound repair. We propose that arginase plays important cell-type specific and temporally-regulated roles in pathological human repair. To test this we will first characterise healing in mice conditionally lacking Arg1 in keratinocytes (K14-cre;Argfl/fl), inflammatory cells (LysM-cre;Argfl/fl) and fibroblasts (Fsp-cre;Argfl/fl). Corresponding mechanistic in vitro experiments will reveal cell intrinsic Arg1 functions. In parallel, we will confirm clinical relevance by assessing L-arginine pathway component expression/activity in a unique resource of human diabetic foot ulcer biopsy tissue with longitudinal healing outcome data; allowing us for the first time to link arginase function and healing outcome. In collaboration with our commercial co-applicant Epistem, we will test the therapeutic potential of L-arginine pathway manipulation to promote healing. We will use both validated pre-clinical mouse models of human chronic healing and ex vivo human wound assays. Our proposal will provide novel insight into the role of Arg1 in skin repair; with the potential for wider translation into other chronic degenerative diseases. By the end of this study we should be in position to move from bench to bedside.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: iRHOM mediated ADAM17 regulation in cutaneous disease and repair
Funder: Medical Research Council

Abstract: Cutaneous wound repair and infection are a major clinical burden . The focus of this proposal will be the investigation of the iRHOM2/ADAM17 pathway in desmosomal regulation and its role in re-epithelialisation during wound healing. From our disease gene discovery programme in monogenic skin and gastrointestinal syndromes, we have identified the first human knockouts for ADAM17 linked to a severe inflammatory skin and bowel phenotype and also "gain of function" mutations in the gene encoding iRHOM2 as the cause of Tylosis (skin disease and oesophageal cancer predisposition). Furthermore we show that iRHOM2 regulates ADAM17 processing and its "shedding" of key substrates including growth factors and pro-inflammatory cytokines. Utilising both patient keratinocytes and molecular biology tools, we demonstrate that iRHOM2/ADAM17 plays a key role in skin barrier maintenance, inflammation and migration. Thus activation of this pathway may be an attractive target for improved chronic and acute cutaneous wound repair.The three main approaches are as follows: 1) Localisation and function of WT and mutant iRHOMs in keratinocyte differentiation:This will investigate the localisation of iRHOMS in the epidermis, the effect of mutation on barrier formation and identify potential iRHOM interacting partners. 2) Dynamics of desmosome formation by iRHOM2: iRHOM2 regulates the sheddase ADAM17. One substrate is desmoglein2, a cadherin of the desmosomal adhesion complex. A number of studies are proposed to innvestiaget iRHOM2/ADAM17 in desmosomal regulation. 3) Human in vitro modelling of iRHOM2 driven wound healing: As our data indicates that TOC associated iRHOM2 mutations are linked with cell phenotypes associated with cutaneous wound healing, the role of iRHOM2 in wound healing will be assessed in a human acute wound model and 3D skin cultures modified genetically.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Developing targeted therapeutics for keratinizing skin disorders
Funder: Medical Research Council

Abstract: State-of-the-art methodologies will be used to study a group of highly debilitating inherited skin conditions called keratinizing skin disorders, for which there are no effective treatments. These diseases are caused by dominant-negative mutations in key epithelial structural molecule genes and are characterized by skin fragility and secondary hyperkeratosis. Collectively, the studies proposed here aim to develop cutaneous delivery systems for current and future therapeutics aimed at skin disorders and identify key molecular regulators of hyperkeratosis. Small interfering RNA (siRNA)-based therapeutics, which selectively inactivate the mutant allele, currently represent the most promising therapeutic intervention for these disorders, but delivering siRNA to the skin is challenging at best. Using a power combination of unique reporter and disease models, we aim to develop non-invasive ways to effectively deliver siRNA-based therapies into the skin. Combining our reporter model with innovative real-time imaging will allow us to rapidly test and fine-tune multiple siRNA formulation-based delivery approaches. The in vivo disease model will then be used to confidently assess, via phenotype resolution, whether these promising formulations effectively deliver potentially therapeutic siRNAs into the skin. This work will provide a strong preclinical data package to facilitate progression to clinical trials in the future. We will use powerful in vivo SILAC-based quantitative proteome profiling techniques to identify the active pathways, key molecular components and cellular processes altered under disease conditions in two, related in vivo hyperkeratosis models. Common key regulators of hyperkeratosis will be identified via molecular validation in an alternative in vivo disease model and a human keratinizing disorder tissue collection. These findings could spearhead the development of a generic treatment for most, if not all, keratinizing skin disorders.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Supporting parents' management of childhood eczema: development of a website based intervention and pilot randomised controlled trial
Funder: Department of Health (England)

Abstract: Objectives1. Explore concerns of parents/carers of children with eczema through qualitative interviews.2. Develop website based intervention to support self-management amongst parents/carers of children with eczema. 3. Carry out pilot RCT of intervention, examining recruitment, randomisation procedures, response rate, outcome assessment, and estimating effect size.4. Randomise participants to: (i) normal care; (ii) intervention; (iii) intervention plus support from health professional to ascertain whether health professional support is needed to use intervention effectively.DesignDevelopment of intervention and pilot feasibility RCT.OutcomesThis research would allow optimal design of an intervention and provide the necessary information to design a phase 3 trial to test this intervention. If shown to be effective, the intervention would improve quality of life for children with eczema and their families and potentially reduce their risk of progression to other atopic disease.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: SKIN
Title: A mathematical model to quantify and help reduce the frictional forces and damage caused by fabrics in contact with human skin
Funder: The Dunhill Medical Trust

Abstract: When a compliant sheet of material is dragged over a convex surface, the frictional forces between them can be many times greater than they would be for a planar interface. This phenomenon is known to contribute to the abrasion damage to skin often suffered by wearers of incontinence pads and bed/chairbound people susceptible to pressure sores. Based on experimental methods and a validated mathematical model we have already created and published, the aim of the proposed project is to further develop and use the mathematical model to study the frictional forces between fabrics and areas of the body known to be particularly susceptible to abrasion damage, such as the hips and the sacrum. Such an understanding is expected to lead ultimately to improved prophylactic and management care of those at risk of incontinence-related and pressure-related skin problems


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: SKIN
Title: Factors modulating the effects of filaggrin haploinsufficiency in ichthyosis vulgaris and atopic eczema.
Funder: Wellcome Trust

Abstract: Eczema is a very common condition, affecting 1 in 8 of the UK population and up to 1 in 4 children. It causes itchy, inflamed skin which can be very distressing. Ichthyosis vulgaris is a genetic condition which produces dry scaly skin and affects about 1 in 250 people. Ichthyosis vulgaris is caused by mutations in a gene called filaggrin (FLG). FLG mutations also significantly increase a person s risk of having atopic (allergic-type) eczema. These FLG mutations are surprisingly common. Th ey are found in 9% of the general population in the UK and nearly half of all children with moderate-severe eczema have one or two FLG mutations. Although we know that FLG is an important cause of eczema, we don t understand exactly what it does in the skin. Not everyone who has FLG mutations develops skin problems but we don t know why. This research is designed to improve our understanding of the FLG gene and how it works with other genes. We think FLG may make give some people eczema that is more difficult to treat with ultraviolet light therapy. If we can understand how FLG works it may, in the long term, help to develop better treatments for eczema.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Functional analysis of Lrig1 and Lrig3 in adult epidermal stem cell self-renewal.
Funder: Wellcome Trust

Abstract: The outer layer of the skin, the epidermis contains cells with specialised function, and some of these are stem cells. Several diseases such as psoriasis and skin cancer affect the epidermis. These disorders are caused by increased cell divisions by stem cells and acquired mutations within these cells. Rodents are the preferred model organisms for human disease, but the obvious differences in the epidermis such as hair makes analysis more complicated. I have identified a new population of stem cells in mouse epidermis, which share properties with human stem cells. My future research will demonstrate whether these are equivalent. In case they are I will be able to investigate how these stem cells behave under normal conditions, when the skin is in need of repair and during disease. In addition I have identified one factor, which is important for regulating these stem cells. I will use my expertise in epidermal biology to identify additional important factors. This will better our unde rstanding of the epidermis but also provide additional targets for molecular intervention such as drugs and therapies for people affected by disorders in the skin as well as in other organs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Functional and molecular characterisation of human keratin 9 to further develop RNAi-based therapeutics for EPPK
Funder: Wellcome Trust

Abstract: The primary aim of this research project is to gain a better understanding of the functional importance and molecular activities of KRT9 in the palmoplantarepidermis so that we may further develop our potential RNAi-based therapeuticsfor Epidermolytic Palmoplantar Keratoderma (EPPK) into clinically applicable treatments. To this end, we aim to: 1. Define the functional importance of KRT9 in the palmoplantar epidermis via generation and characterization of KRT9knockout mice. 2. Establish an in vitro PPK culturing system for evaluating novel therapeutics and characterizing the molecular activities of KRT9. 3. Explore and develop in vivo siRNA delivery methodologies for therapeutic treatment of EPPK.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: SKIN
Title: Identifying the network of lipid mediators responsible for maintenance and resolution of ultraviolet radiation-induced skin inflammation.
Funder: Wellcome Trust

Abstract: Exposure of human skin to solar ultraviolet radiation (UVR) results in acute inflammation that contributes to skin damage, photosensitivity, premature skin ageing and photocarcinogenesis. We have reported that early stages of UVR-induced inflammation (sunburn) appear regulated by sequential temporal changes in eicosanoid production. However the later stages of sunburn, including its resolution phase, have not yet been studied. The aim of this project is to identify the network of bioactive l ipid mediators responsible for maintaining and resolving the UVR-induced human skin inflammation and assess the impact of photoprotective bioactive polyunsaturated fatty acid (n-3PUFA) nutrients on its progress. Our goals are to evaluate (a) the time course of production of lipid mediators during and until resolution of sunburn, and compare the response of people who burn easily to those who are more resistant, (b) the effect of n-3PUFA nutrients on the magnitude and time of inflammation resol ution, (c) the expression of key lipid metabolising enzymes, and (d) the contribution of individual cutaneous cell types to these effects. Understanding the mechanisms maintaining and resolving the normal sunburn response will facilitate identification of biomarkers, inform strategies to reduce the damaging effects of solar radiation and may lead to the discovery of resolving agents.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: RhoE functions in the specification of stratified epithelia .
Funder: Wellcome Trust

Abstract: Epithelial cells form an important component of many different tissues and organs in the body. In particular, the epidermis, the outermost part of the skin, is an important organ that prevents water loss and protect from invasion of pathogens. Mice in which genes relevant for epidermal architecture and function are deleted die soon after birth, mostly due to dehydration. Thus, it is important to understand how the epidermis is properly formed and prepared for its important function during adu lt life. The epidermis is a stratified epithelium and consists of multiple layers of cells arranged in an orderly manner: they attach tightly to each other to provide water impermeability. The orderly organization of epidermal architecture is severely perturbed in inflammatory and hyper-proliferative diseases of the skin. The precise mechanisms via which epidermal cells selectively detach from the basal layer and migrate upwards during epidermal differentiation are not known. We found a s ignalling protein RhoE that, when expressed, enhances the ability of cells to form suprabasal layers. Understanding how RhoE can promote stratification and differentiation will potentially indicate strategies to reduce the disruption of epidermal architecture that is associated with atopic or chronic forms of skin diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN
Title: Reciprocal signalling between epidermal stem cells and their neighbours.
Funder: Wellcome Trust

Abstract: My lab studies stem cells in the epidermis, which is the outer covering of the skin. The epidermis provides the protective covering of our bodies and every day millions of the protective cells in the outermost epidermal layers are shed from the surface of the skin. Stem cells are responsible for maintaining the epidermis by dividing to replace the cells that are lost each day. The goal of my Wellcome Trust award is to understand how epidermal stem cells exchange signals with other cell types in the skin, such as fibroblasts, pigment cells and fat cells. This will help us to discover how the skin functions normally and, in addition, it will provide information about changes in the skin that occur during wound repair, ageing and disease. Our work is relevant to a wide range of skin disorders, including hair loss, scar formation and cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Dermatology and Genetic Medicine: A multidisciplinary research initiative aimed at translating basic science discoveries in genetic skin disease into clinical application.
Funder: Wellcome Trust

Abstract: Dermatology is an under-resourced area of medical research. Despite this, the University of Dundee has established a critical mass of internationally-reknowned, award-winning researchers in genetic skin disease and dermatology therapy development. This project will strengthen this group of biologists, dermatologists, physicists and drug discovery scientists and help us take this to the next level treating patients with revolutionary new drugs rationally designed to target specific genetic ski n disease. This includes the most common skin condition, eczema, where defects in the filaggrin gene, carried by 10% of the population are a leading cause of disease. Using new DNA sequencing technology, we will identify most of the remaining genes in rare, severe skin diseases and in eczema. A professionally-managed drug discovery team, dedicated to dermatology targets, will perform 15 drug screens, supported by industrial-style medicinal chemistry, with the aim of taking at least 2 new derm atology therapies through to pharmaceutical partnering and into the clinic. Animal models and in vitro human skin cultures will allow testing of new therapies to facilitate future human clinical trials. This research centre award will also strengthen our capacity for patient outreach and training of new investigators in dermatology research.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN