NIHRDataInsights/HRCSData huggingface dataset:
Title: Developing a Rat Analogue of a Human Transglutaminase 2 Inhibitory Antibody to Facilitate Preclinical Testing in Treating Kidney Fibrosis
Funder: Medical Research Council

Abstract: Background: Transglutaminase 2 (TG2) is central to the development of kidney fibrosis. No specific inhibitor exists. We have therefore developed TG2 inhibitory antibodies targeting 4 defined epitopes in human TG2. These do not inhibit mouse or rat TG2 effectively & are subsequently unsuitable for pre clinical testing. Purpose: To generate recombinant TG2 antibodies targeting the corresponding inhibitory epitopes in mouse & rat. Undertake preclinical testing of these antibodies as anti-fibrotic agents. Antibody generation: A scFv phage library will be constructed from the spleens of TG2 KO mice immunised with rat TG2. Phage selection will be used to isolate mAb sequences binding to known inhibitory epitopes. Selected clones will be used to produce inhibitory antibody fragments by recombinant methods, and validated in cell systems In vivo application in kidney fibrosis: The best 2 mAbs will be applied to the mouse unilateral ureteric obstruction (UUO) model of kidney fibrosis to provide early proof of principle data on TG2 inhibition, fibrosis & collagen accumulation. The UUO model is rapid, but does not provide functional data & fails to demonstrate typical glomerulosclerosis and tubulointerstitial fibrosis. To address this mAbs will be applied to the rat subtotal nephrectomy model of kidney fibrosis. This is the chronic kidney disease model recognised by the FDA, allowing measurement of function (creatinine clearance, albuminuria) and showing features of human kidney fibrosis (collagen accumulation, fibroblast proliferation, loss of architecture). To achieve this, a series of rat chimeras of the mouse antibodies will need to be generated by framework exchange (MRCT). Other fibrotic diseases: To demonstrate these therapeutic antibodies have a wider application in the treatment of fibrotic disease, they will be applied to the bleomycin model of pulmonary fibrosis, with lung function (dynamic compliance, blood gasses), collagen & fibrotic index measured.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY;RENAL AND UROGENITAL
Title: Modelling bronchopulmonary dysplasia through human lung progenitor organoids and mouse xenotransplantation
Funder: Wellcome Trust

Abstract: Bronchopulmonary dysplasia (BPD) is a chronic respiratory system disease with a particularly high incidence in preterm infants who receive mechanical ventilation and oxygen supplementation. BPD is characterized by less developed alveoli, the main gas exchange region. Clinical studies and animal experiments have identified hyperoxia exposure, ventilation trauma and genetic susceptibility as risk factors of BPD, though their effects on human alveolar development at a cellular level remain unknown. Based on the established progenitor organoid system derived from human embryonic lung tips, I aim to build an in vitro alveolar differentiation model and investigate the effects of BPD risk factors on this process. I will also use a mouse xenotransplantation model to assess the in vivo differentiation potential of human lung progenitors affected by BPD risk factors. These studies will help to delineate the impact of current respiration-supporting methods on human alveolar development. The elucidated cellular and molecular mechanisms can assist to reduce the risk and damage of BPD on preterm infants and improve long-term health conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Enabling Research Award: Getting it right; devising an optimal implementation plan for a paediatric ventilator weaning trial.
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: There were no significant differences between arms by CD4 response (p=0.21), numbers of serious complications (p=0.15) or change in neurocognitive function (change in mean NPZ-score, p=0.86). However, there were less grade 3/4 serious events in the monotherapy group [n=137 vs 159 (46% vs 55%; difference, -8.4%; 95%CI -16.4% to 0.3%), p=0.043].


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RESPIRATORY;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The effects of antenatal micronutrient supplementation and current air pollution on growth and lung function in 8 year old children.
Funder: Wellcome Trust

Abstract: This research will help to show if the diet of the mother during pregnancy can affect the size of their child and their ability to breathe when they are eight years old. We will do this by following up the children born to a group of women were given a vitamin and mineral supplement during pregnancy and another similar group who were not. We will measure the size of the children and try to estimate what their body is made up of. This will show if any differences in size are due to a diffe rence in fat or muscle quantities. We will then look at the capacity of their lungs and measure the quality of air they are breathing in and the current mineral levels in their body. This will tell us if the supplement in pregnancy is associated with a difference in their ability to breathe. If this is so, can it also protect against the harmful effects of air pollution? Word count = 162


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: RESPIRATORY;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Molecular and cellular mechanisms of mouse fetal lung maturation.
Funder: Wellcome Trust

Abstract: Our lungs are highly complex organs with a precise structure which must be generated during embryonic development. The lung is one of the last organs to form in the embryo. When babies are born prematurely the last steps in lung embryonic development do not occur and these individuals can suffer from breathing problems throughout life. The long-term goal of our research is to find a way to correct these lung development problems after birth. As the first step towards this goal, we aim to identif y the genes used during the final phase of lung embryonic development and to test their function in the adult lung.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: RESPIRATORY;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Clinical utility of a CRTH2 antagonist, OC000459, as an anti-Th2 therapy in atopic dermatitis
Funder: Innovate UK

Abstract: This study will evaluate a novel anti-Th2 therapy as a controller treatment of moderate-to-severe atopic dermatitis with the primary objective to prevent occurrence of disease flares, the major healthcare burden. OC000459 is an orally administered drug that inhibits the receptor CRTH2 expressed by Th2 lymphocytes, eosinophils and basophils. CRTH2 mediates recruitment of these leukocytes to inflamed skin and their activation to elaborate Th2 cytokines. CRTH2 is also implicated in the process of allergic sensitisation and its inhibition may therefore have long lasting disease modifying activity with the potential to halt the atopic march. OC000459 has proven efficacy in asthma and allergic rhinoconjunctivitis and therefore has the advantage of treating multiple co-morbid allergic diseases as a single systemic treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: SKIN
Title: Feasibility of developing innovative processes to improve the manufacturing logistics of cell therapy
Funder: Innovate UK

Abstract: Cell Therapies hold the promise to treat a great many diseases, however one limiting feature of providing a living cell therapy is the realtively short shelf life of the products. This project aims to test the feasibility of using two different, innovative process changes to extend this shelf life considerably which would greatly impact how Intercytex's, and possibly others manufacture cell therapies. Success in this project will lead to additional studies by Intercytex to allow this process to be used for patient treatment. It will allow the Company to have product ready on demand for clinicans to treat the severe blistering disease Epidermolysis Bullosa and scar contractures.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: SKIN
Title: A novel treatment for eczema using a substance derived from sunflower-seeds
Funder: SPARKS

Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 15 to 20% of children. AD is a multi-factorial disease caused by complex interactions between genetic and environmental factors. It is now widely accepted that primary skin barrier abnormalities is a ‘driver’ for the onset and development of AD. Kallikreins, a group of serine proteases involved in skin barrier formation and function are persistently high in AD skin. The pathological change can cause unrestricted, kallikrein-dependent degradation of corneodesmosomes in keratinocytes, resulting in skin barrier dysfunction. This seems to create a strong rationale for the development of specific therapeutic strategies for AD. We propose to develop an effective treatment for AD using a serine protease inhibitor that can selectively modulate kallikrein activity. Inhibitor analogues derived from naturally occurring peptides sunflower trypsin inhibitor (SFTI) will be synthesised and tested using high throughput inhibitory assay. The inhibitory effect of the most potent SFTI analogue will further be examined in cell model and in an in vitro 3D skin equivalent culture model. We anticipate that the effective SFTI analogue can be used not only for AD, but also for other skin conditions requiring a similar therapy such as genetic skin disease Netherton syndrome.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: SKIN
Title: the manufacture of a flexiBle blAnket that will provide phototherapy treatMent for a numBer Of cOnditions (BAMBOO)
Funder: Innovate UK

Abstract: Project BAMBOO will develop a wearable and flexible phototherapy device for the treatment of a number of medical conditions including but not limited to wound healing, neonatal hyperbilirubinia or Psoresis. The device will be produced by printing methods it will incorporate sensors to allow the measurement of disease progression, monitor infection and manage dosage.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: SKIN
Title: Micro-patterned polymer substrates as novel models of epidermal wound healing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The overall objective of the proposed research is to determine how human keratinocytes sense and respond to changes in their environment during wound healing. Micro-contact printing techniques will be used to create a novel in vitro model of epidermal wound healing. Micro-patterned substrates will consist of islands of protein resistant polymer brushes, which will serve as model 'wound beds', and will be surrounded by confluent human keratinocytes. Migration into the wound will be activated by coupling specific extracellular matrix proteins to the polymer brushes. This system will allow us to precisely control the size, shape, and composition of the wound bed. In addition, this assay will be used to investigate the role of serum response factor (SRF) signalling in keratinocyte mechano-sensing during the wound healing process. This work will be carried out in three specific aims and test two major hypotheses: (1) The composition and structure of the wound bed regulates re-epithelialization via altered migration and proliferation of the keratinocytes. (2) SRF mediates cellular responses to physical cues during epidermal wound healing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Use of Synthetic Biology in the Development of Bacterial Adhesins for Skin Grafting applications
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Since the 1980's cultured tissue engineered keratinocytes have been used to treat burns and chronic wounds. However, cultured cells usually fail to attach well to challenging wound beds, as are often present in burns or chronic non-healing ulcer patients. These wound beds are characterised by poor vasculature and a dearth of extracellular matrix proteins that ensure attachment of the epidermis to dermis (i.e. Collagen IV, VII and laminin). They contain predominantly Collagen I, are rich in degradative enzymes, sometimes infected and usually poorly vascularised. Even conventional split-thickness skin grafts can fail to attach well on such wound beds. We aim to produce a 'bioglue' targeted at attaching split thickness skin grafts or cultured cells to collagen I. This bioglue must increase adhesion in these situations and persist in the body long enough (5-10 days) for adhered skin cells to begin remodelling wound beds, promote vasculature and ultimately restore barrier function. Our approach is to use a synthetic biology pathway to redesign the bacterial flagellum to produce adhesive protein fibres. We have redeveloped the flagellin molecule into a modular adhesin presentation device comprising the D0 and D1 polymerisation domains but lacking the central domains D2 and D3. This device has been engineered to accept a range of adhesin domains from bacteria and humans in a modular fashion via restriction sites. After biochemical characterisation, these will be introduced into our poor wound bed model, lacking basement membrane and fibroblasts and growth/ adhesion of cells assessed. We have engineered a prototype flagellin device to carry a module comprising the cna adhesin from Staphylococcus aureus and shown that it binds collagen I and promotes adhesion of a Skin cancer cell line to tissue culture plastic. In this proposal we will take to the next stage of testing and improve both yield, purity and efficacy while also reducing any potential immunogenicity.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: SKIN
Title: Role of Satb1 in the control of topological genome organization during skin development and ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Epigenetic mechanisms play an important role in the control of organ development and regeneration. Understanding how and why these mechanisms are altered during ageing and in many age-associated disorders (cancer, impaired wound healing, etc.) has become a growing priority in biomedical research. Progress in the genome and chromatin biology achieved within the last two decades revealed that higher-order chromatin remodelling and establishment of specific long-range arrangements of the genes from the same or different chromosomes in three-dimensional nuclear space are important for proper control of cell differentiation and organ development. In this proposal, we will use a complex approach including 4C chromatin conformation capture technology, 3D-FISH and genetically modified mouse models to test a hypothesis that the genomic neighbourhood of lineage-specific genes is functionally important for proper execution of differentiation programs in epidermal progenitor cells and that genome organizer Satb1 regulates the establishment and remodelling of such neighbourhoods in keratinocytes during development, postnatal growth and ageing. This project will address two Specific Aims: 1. Define the basic principles that control the organisation of the genomic neighbourhood of lineage-specific gene loci in epidermal keratinocytes and its functional significance during normal development, postnatal growth and ageing. 2. Define the role of genome organizer Satb1 in the establishment of distinct genomic neighbourhoods for lineage-specific gene loci in epidermal keratinocytes during development and its remodelling during ageing. This project will help in better understanding the complexity of regulatory mechanisms that control development and ageing, as well as in designing new approaches on how to modulate skin ageing by targeting Satb1 and correcting age-associated alterations of gene expression programs in keratinocytes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Investigation of the role of cellular senescence in skin aging using in vivo and in vitro approaches
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Transcriptomic studies comparing chronologically and photo-aged skin have shown that convergent pathways implicating loss of ROS homeostasis, increased expression of pro-inflammatory markers, reduced expression of epidermal differentiation markers and impaired cholesterol lipid biosynthesis are key features of skin ageing. We propose to refine this data by performing a six decadal cross sectional analysis of human skin ageing. We will use laser capture micro-dissection in combination with transcriptomic and immunohistochemical analyses to map and then model the interaction of age dependant changes in all compartments of human skin. The data already available to us are consistent with our hypothesis that the gradual accumulation of senescent dermal fibroblasts contributes to skin ageing via a senescence associated secretory pathway (SASP) including leakage of ROS and secretion of pro-inflammatory molecules that causes bystander effects in both the dermis and the epidermis. To test this hypothesis we have developed a 3D organotypic skin equivalent that recapitulate several aspects of skin ageing, including epidermal thinning, delayed development of a cornifed envelope and altered cell cycle kinetics within transit amplifying cells. Importantly these epidermal changes are caused by the presence of aged or prematurely aged fibroblasts in the dermal equivalent. We will refine this model so that it can be used to both test the hypothesis that a SASP in the dermal equivalent of the model drives epidermal senescence via a bystander effect and to investigate which elements of skin ageing are caused by dermal senescence. Importantly, we will use to use inhibitors of SASP, already available in our laboratories, as a possible means of either slowing or even reversing ageing phenotypes in the model. In the long term we will use the model to develop and test new skin rejuvenation products.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: SKIN
Title: Skin barrier impairment in early life and the development of sensitisation and eczema: epidemiology, gene-environment, interaction and immunology
Funder: Department of Health (England)

Abstract: Background: The recent discovery of the filaggrin skin barrier gene has led to the hypothesis that predetermined skin barrier dysfunction together with environmental factors, such as excessive use of soap and detergents, leads to clinical eczema. Objectives: This project for the first time, examines the role of skin barrier dysfunction, determined both genetically (filaggrin mutations or other skin barrier gene mutations) and phenotypically (transepidermal water loss), in the development of allergic sensitisation and clinical eczema in a large population-based birth cohort study. Gene-environment interaction as well as the immunological events related to genetic mutations, allergic sensitisation and clinical eczema will be studied. Study design, methods and outcomes The Children's Allergy and Dermatology Unit, Evelina Children's Hospital, Kings College London has recently been awarded a grant from the FSA/MRC to conduct a 2,500 mother-infant pair birth cohort study. This randomised study will examine the effect of early introduction to allergenic foods at 3 months versus exclusive breast feeding until 6 months of age on the cumulative prevalence of allergenic sensitization and food allergy at 12 months and 3 years (FSA Grant no T07051. My study will utilize this clinical resourse to examine the above objectives. Cord blood specimins will be taken and children will also donate blood and will be skin prick tested at 3 and 12 months. Cord blood will be screened for FLG mutations as well as other putative genetic polymorphisms associated with impaired skin barrier function. Outcomes are clinical eczema (questionnaire-derived and skin exam) and allergenic sensitisation (raised specific IgE or skin prick test positively) at one year of age, as well as transepidermal water loss (skin barrier impairment). In addition, we will measure Th1 and Th2 cytocine profiles at birth, 3 and 12 months.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: SKIN
Title: The Baby Olive Oil and Sunflower Oil Skincare Trial (BOOST Study): A pilot, assessor-blinded, randomised controlled trial, to assess the impact of olive oil and sunflower oil on a term baby's skin barrier function.
Funder: Department of Health (England)

Abstract: Title: The use of Oil in Baby SkincaRE (OBSeRvE) Pilot Study. Background: Oil is recommended and widely used for baby skincare. Some topical oils may impair skin barrier function and contribute to the development of childhood atopic eczema. Objectives: To test the hypothesis that regular application of sunflower oil, when compared with no oil or olive oil, improves the skin barrier function of newborn term babies. Design: Pilot, assessor-blinded randomised controlled trial and nested qualitative study. Expected Outcomes: Primary: change in spectral profile of lipid lamellae assessed by infrared spectroscopy. Secondary: basal trans-epidermal water loss (TEWL), skin hydration, skin surface pH and clinical observations. Anticipated Benefits: Proof of concept, feasibility, acceptability, and trial parameters for a full trial.


Research activity codes: 6.8 COMPLEMENTARY
Health categories: SKIN