NIHRDataInsights/HRCSData huggingface dataset:
Title: Immune causes of chronic inflammation in uveitis.
Funder: Wellcome Trust

Abstract: My research is about uveitis, a sight-threatening disease due to abnormal inflammation within the eye caused by the body's immune system mistakenly attacking it. If more was known about why uveitis persists, we could develop more effective treatments. My research is designed to address this. My theory is that in uveitis the eye becomes full of immune system cells. Instead of being randomly distributed throughout the eye, I think the immune system cells are being organised into clusters. This may make uveitis persistent. The experiments I plan involve mice with uveitis. Eye samples are taken, the immune system cells in the eye analysed using chemicals that label them, a microscope and other equipment to sort the cells according to what kind of cell they are. The levels of chemicals in the eye that organise immune cells will be measured. I will analyse a small number of human eyes also. My research will provide evidence for my theory that organisation of the immune cells within the eye affects uveitis, and thereby benefit patients by informing further research that will enable the development of new treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: Development of a therapeutic antibody for a novel angiogenic target
Funder: Medical Research Council

Abstract: Neovascularisation and vascular remodelling are key clinical features of several pathologies, including wet age-related macular degeneration (AMD), solid tumours and diabetic retinopathy. Regulation or inhibition of vascular changes in these conditions has been shown to slow or arrest disease, but the number of anti-angiogenic therapeutics available is limited, their efficacy is patchy, and the field is constrained by the paucity of useful molecular targets. We have identified a protein of previously unknown function that we have shown to be a potent regulator of angiogenesis. The protein stimulates endothelial cell tube formation in angiogenesis assays, and its activity can be blocked by specific peptides. The aim of this proposal is to i) develop a function-blocking antibody against the protein, ii) demonstrate the efficacy of the antibody in murine models of retinal vascular disease, and iii) develop a humanised version of the antibody for subsequence evaluation in clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: EYE;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: Retinal bioimaging for neurodegenerative and cardiovascular diseases
Funder: Medical Research Council

Abstract: Aim To identify the most accurate retinal biomarkers predictive of of incident CVD events and AD Objectives 1) Examine the relationship between retinal lamellar parameters and incident myocardial infarction and cerebrovascular accidents using the AlzEye database 2) Validate the association between retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness with incident AD 3) Leverage the UK Biobank cohort for adult life course epidemiological analysis of CVD and AD risk factors and external validation 4) Development of a convolutional neural network predicting risk of CVD events and AD to identify novel biomarkers Methodology Analysis will be conducted using two curated large datasets - the UK Biobank and AlzEye, a pseudonymised dataset of >2 million optical coherence tomography (OCT) scans of 250,000 patients from Moorfields Eye Hospital. Fundus photographs and OCT scans will be analysed using automated segmentation and image analysis software. Regression techniques and survival modelling will evaluate the hypothesis that specific retinal changes are indicative of incident AD and CVD events. Convolutional neural networks on outcome data with OCT and fundus photos as inputs from the AlzEye dataset will be developed and leveraged as tools to identify structural biomarkers through spatial soft attention maps. Models will be externally validated using the UK Biobank Cohort. Scientific and medical opportunities Improving our understanding of retinal manifestations of two major epidemics of the developed world, cardiovascular disease and AD, may potentially refine risk stratification techniques with in-vivo evaluation. Identification of any biomarkers would also allow non-invasive measures of efficacy in any future interventional clinical trials assessing treatments in CVD or AD. Broader implications of the feasibility of linked healthcare research and the impact of real-world studies on healthcare policy will also be explored.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: EYE;CARDIOVASCULAR;NEUROLOGICAL
Title: Developmental Disorders: From Diagnosis to Mechanism via Cis-Regulation
Funder: Medical Research Council

Abstract: Our research group, led by David FitzPatrick, an academic paediatric geneticist, focuses on understanding the genetic basis of severe developmental disorders Major aims are identification of genetic causes of major eye malformations and a severe intellectual disability syndrome; Cornelia de Lange syndrome (CdLS). Following their discovery that a major cause of severe bilateral eye malformations is de novo formation of heterozygous, loss-of-function mutations in SOX2, they have used exome sequencing to identify several novel loci such as YAP1 and MAB21L2 for severe bilateral coloboma. They have also identified genetic changes in BRD4 as a novel cause of CdLS. A common theme of this work is the innovative use of genetic technologies to identify and validate causative mutations affecting the structure or regulation of individual genes. The major focus of the future work is the use of whole genome sequencing and cell and animal models to understand the impact of genetic changes in enhancers of dosage sensitive transcription factors in developmental disease. We have 3 major aims as follows: 1) Identify and categorise highly penetrant genomic mutations causing human eye malformations using family-based whole genome sequencing (WGS) and whole exome sequencing (WES) with particular focus on interpreting changes in the noncoding genome 2) Develop broadly applicable approaches to integrate the available clinical genomic data with quantitative (growth, developmental milestones) and categorical (HPO terms) phenotypic features to improve the diagnosis of known diseases and the discovery of new genes/genetic mechanisms. 3) Define the functional genomic characteristics of the transitions in gene regulatory networks (GRN) driving very early eye development using in vitro (human embryonic stem cells differentiation) and in vivo (zebrafish embryogenesis) approaches both to improve our understanding of tissue-specific transcription factor function and to identify interpretable targets for non-coding mutations causing major eye malformations in the human genome.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;GENERIC HEALTH RELEVANCE
Title: Sotilis Nousias - Ophthalmic Medical Imaging PhD studentship
Funder: Moorfields Eye Charity

Abstract: This fellowship is investigating light-field technologies as a way to acquire more information during ophthalmic observations. Light-field cameras are a novel technology that capture images through a set of micro-lenses, rather than a single lens. This image capture approach allows one to refocus the image after it has been taken, create novel viewpoints, and extract 3D structure. Sotiris work contributed to the creation of a light-field ophthalmoscope prototype (published at SPIE BIOS). During this prototype construction work it was realised that the mathematical framework behind processing light-field images is not well understood. Therefore, he is now focusing on developing mathematical tools that allow the calibration of light-field cameras (published at ICCV) and the 3D reconstruction of scenes from light-field cameras, while supporting a post-doc with optics development background in the creation of the second light-field ophthalmoscope prototype.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: EYE;GENERIC HEALTH RELEVANCE
Title: Dropping the Needle: Injection-Free Drug Delivery to the Eye
Funder: Dunhill Medical Trust

Abstract: Age-related macular degeneration (AMD) is a leading cause of vision loss in Europe and the US. Current therapy for neovascular AMD consists of monthly intravitreal injections of anti-VEGF antibodies for a minimum of 5 years. For most patients it is an effective therapy, however, it has significant side effects, including uveitis, retinal detachment, and raised intraocular pressure. There is a unmet clear need for topical applications that can be applied by the patient themselves anywhere. However, the eye poses significant barriers to drug delivery as the structures of the eye act as barriers to the penetration of drugs. Our preliminary work has investigated the use of biogenic polyamines as membrane penetrating drug delivery agents. Using both a membrane translocation model and an ex-vivo porcine eye model, we have that they are able to translocate and deliver significantly higher concentrations of drug molecules than existing technology built on polyarginine cell penetrating peptides (CPP) which are currently in development. We have also shown that both large (150 kDa), and small proteins (2.9 kDa) used in anti-VEGF therapy can be successfully transported using these polyamines. The aim of the work described in this proposal is to fully characterise the MPPA delivery system, while also elucidating the mechanism of delivery. Once this complete, the MPPA will undergo cytotoxicity validation and preclinical testing to provide the necessary dossier of information for regulatory approval from MHRA. for a clinical trial.

Lay abstract: Our research aims to treat a common form of sight loss using eye drops instead of injections. Age-related macular degeneration (AMD) is a painless condition that becomes increasingly common in people aged 50 or over. About 1 in 50 people aged 50 or over have some form of AMD, increasing to nearly 1 in 10 for people aged 85 or over. Usually vision loss is gradual and happens over a period of years, but sometimes vision loss can be rapid, happening over several weeks. The macular region is a part of the retina where the most detailed images are formed. Its loss makes activities such as reading, driving and recognising faces very difficult. Some forms of AMD can be treated, but doing so requires monthly injections into the eye for at least five years. This treatment works well for most people, but requires regular outpatient visits and there is a small risk of additional complications from the injection process itself. We have developed a method to improve treatment by using molecules that naturally occur within the body to package and deliver the same drugs that are currently injected into the eye as eye drops instead. This has the potential to make treatment safer and more convenient for patients and less costly for the NHS as eye drops can be administered by the patient themselves when and where they choose to.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: EYE;GENERIC HEALTH RELEVANCE
Title: Targeting Exotoxin U with repurposed drugs to improve the clinical outcomes of Pseudomonas aeruginosa infections.
Funder: Medical Research Council

Abstract: Exotoxin U (ExoU) is significantly linked to poor outcomes of Pseudomonas aeruginosa infections. It is a phospholipase injected into host cells, which causes rapid destruction of tissue and evasion of the immune system. We hypothesis targeting ExoU with drugs could provide a novel therapy that improves clinical outcomes. We have identified 25 promising drugs which inhibit ExoU. In vitro cell models demonstrate they reduced cell lysis and promote healing. A synergistic effect is also shown with some conventional antimicrobials. This project aims to establish the efficacy and pharmacokinetics of ExoU inhibitors, specifically their ability to reduce tissue damage in cell, ex vivo and in vivo models. Utilising scratch and infection models of human corneal (HCE-t) and human lung epithelial (A549) cell lines, I will determine which compounds reduce the cellular damage associated with ExoU, with and without additional antimicrobials. Cellular responses will be quantified by lactate dehydrogenase, trypan blue uptake and propidium iodide uptake assays, alongside live-cell and immunoflourescence imaging. Human donor cornea attached to an artificial anterior eye chamber model will be used to demonstrate the concentration of drugs which penetrate through the cornea. Concentrations will be estimated using a phospholipase assay compared with a standard curve and a select number will be quantified and validated using liquid chromatography-mass spectrometry. Treatment protocols for future work will be established using an ex vivo porcine corneal infection model. Different concentrations and combinations of drugs will be tested, with and without antibiotics. Over 72 hours, clinical scoring, colony forming units (CFU) counts and histology will be analysed. Finally, an ethically approved in vivo murine model of P. aeruginosa corneal infection will be used to establish safety and efficacy data using clinical scoring, CFUs and histology.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: EYE;INFECTION
Title: The Retinal Microvasculature in Cerebral Malaria in African Children.
Funder: Wellcome Trust

Abstract: We will study the eye to gain better knowledge of the causes of death and long term damage in children with cerebral malaria (CM). Studies into different aspects of the field will link with each other and develop over five years. Methods of measuring changes due to CM visible on retinal photographs will be developed. These will be compared with damage to the brain visible on magnetic resonance images (MRI) during coma. The eyes of children who die will be studied to identify the nature of the retinal changes, particularly what appears to be sequestration, one of the main ways that the malaria parasite causes harm. We will investigate the type of damage done to the retinal tissue especially looking at the effects of shortage of oxygen. Children who survive will be tested annually for damage to their sight and for delayed development over a series of annual visits and compared to normal children. New ways of doing these tests will be developed. Finally we will test in the lab oratory how the malaria parasite behaves in the eye by studying how it makes red blood cells stick to and damage the inner lining of the blood vessels in the retina.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: EYE;INFECTION
Title: Studies in the pathophysiology and management of corneal necrosis in severe microbial keratitis
Funder: Wellcome Trust

Abstract: Microbial keratitis, caused by bacterial or fungal infection, is a major cause of blindness worldwide. Despite adequate antimicrobial therapy, severe corneal inflammation frequently progresses, resulting in corneal necrosis, thinning and perforation. Although the pathophysiology of this process has not previously been investigated in detail, it is likely that matrix metalloproteases (MMPs), produced by the inflammatory cell infiltrate and possibly the microorganisms themselves, play a major role in corneal destruction. Through inhibition of MMP action, it may be possible to limit corneal destruction and ameliorate wound healing, to improve outcomes in severe infective keratitis. The antibiotic doxycycline is a known broad-spectrum MMP inhibitor, which is used extensively in ophthalmology to control ocular surface inflammation and to limit corneal necrosis after chemical injuries. We propose to conduct two randomised placebo-controlled trials (i. Bacterial; ii. Fungal) to determine the efficacy of doxycycline in reducing the incidence of corneal perforation in severe keratitis. In addition, we will conduct a set of related studies into the pathophysiology on corneal necrosis. Microarray analysis of perforated corneal tissue (compared to donor cornea) will be used to identify major pathways and factors activated in this disease and guide the choice of targets for detailed study with quantitative RT-PCR, protein detection and immunohistochemistry. We will also evaluate in vivo confocal microscopy in the diagnosis of infection and monitoring of treatment and inflammatory response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: EYE;INFECTION
Title: Inflammation and Immunotherapy
Funder: Department of Health and Social Care

Abstract: AIM 1: Dynamically visualise ocular immunity in man (“immune-imaging”) Objectives 1-2 years Proof-of-concept studies for single-cell visualisation of fluorescently-labelled cells in the living human retina and preliminary development of novel imaging endpoints for ocular inflammatory diseases. 3-4 years Simultaneous visualisation of two or more fluorescently-labelled cell types. 5+ years Generate a leukocyte-directed fluorophore-tagged peptide library for visualisation of multiple cell types in the human retina and pull-through of novel immune-imaging outcome measures. AIM 2: Expand our pipeline of future ocular immuno-therapies (“immune-therapeutics”) Objectives 1-2 years Phase 1 anti-LRG1 antibody clinical trial in AMD. Pre-clinical development of a novel antibody fragment(Fab)-drug conjugate (patent PCT/GB2014/053804) for selective suppression of adaptive immune memory and a bispecific anti-IL-6 / anti-TNFα antibody. 3-4 Years Proof of concept for IL-18 and IL-33 prevention of angiogenesis and optimisation of retinal health prior to stem cell and gene therapies. Epigenetic drug and immune tolerance peptide selection. 5+ years Develop a portfolio of drug candidates in advanced clinical development, which selectively and simultaneously modulate multiple mechanistic targets for precision immunotherapy (stratified by disease and patient immunophenotype). AIM 3: Immune profile patients with ocular inflammatory diseases (“deep immune-phenotyping”) Objectives 1-4 years: Modify the human immune-phenotyping protocols developed by the NIH Centre for Human Immunology (UNITE consortium) and the Pasteur Institute for application in ocular inflammatory diseases (including multi-parameter flow cytometry and functional transcriptomics). 5+ years: Application for patient stratification and the acceleration of early drug development (in concert with Aim 2).


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: EYE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Characterisation of a novel innate-like T cell in the eye as a target tissue in uveitis, spondyloarthropathy (SpA) and related diseases
Funder: Medical Research Council

Abstract: Our aim is to characterise the molecular interactions and cellular atlas of uveitis directly within human uveal tissue. using 10x genomic analysis. We aim to present a map of cellular populations in uveitis, cell-cell interactions and expression of differentially regulated genes. Objectives 1.1 Four large ophthalmic surgical centres will collect uveal samples from glaucoma patients undergoing trabeculectomy with uveitis and those without. 2.1 Disaggregated uveal tissue will be subjected to scRNA-seq and V(D)J analysis using the 10x Genomics platform 2.2 ScRNA-seq data will be analysed using bioinformatics pipelines set out http://www.github.com/sansomlab/tenx), based on Cellranger (10x Genomics), Scater and Seurat workflows to phenotype cells enriched in uveitis following cluster analysis. 2.3 Differentially expressed genes between uveitis and controls within clusters will be identified and then subjected to a functional bioinformatic pipeline including GSEA 2.4 We will investigate cell surface markers for T cell populations including gdT cells and for the expression of cytokines and cytokine receptors in uveitic samples and compare these to non-uveitic samples. 2.5& 2.6 Following this, we will seek expression of GWAS-assocated genes for anterior uveitis and study V(D)J sequencing information to investigate clonal expansion withinT-cell subpopulations in uveitis. Finally, we will compare our results to published data for other tissues involved in spondyloarthropathies. 3.1 Validation of scRNA results will be by FACS analysis (BD LSR, LSR Fortessa X20 ) which will be performed on cell surface markers which are significantly altered in uveitis as well as standard markers for T cell phenotypes and TCR clonotypes. 3.2 CODEX multiparameter immmunofluorescence and confocal microscopy ( Zeiss 880 Airyscan ) will be performed upon paraffin-embedded uveal tissue and fresh frozen sections. Images will be analysed with proprietary software,Zen and Image J.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Pathways to fibrosis in Graves' orbitopathy
Funder: Medical Research Council

Abstract: Graves' orbitopathy (GO) is a disfiguring and sight-threatening complication of Grave's disease, in which immune-mediated inflammation of the orbital contents progresses to tissue fibrosis. Whilst it is established that activating antibodies against the TSH receptor are central to GD, not all patients with GD develop GO, even in the presence of severe hyperthyroidism. We hypothesize that subsets of stromal cells and local antibody production drives GO, and mediates transition to tissue fibrosis. To explore these hypotheses we will uncover the cellular landscape of the disease in its acute and fibrotic phases, using single-cell analysis of transcriptome, surface markers, and immune repertoire, in biopsy tissue and peripheral blood. We will study novel stromal cell subsets, and express pathogenic antibodies, determining their interactions with fibroblasts in functional experiments. This work will address fundamental mechanistic questions in immune-driven fibrotic disease, and has the potential to uncover new therapeutic targets for GO.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating retinal vasculopathy pre-COVID-19 as an independent risk factor predictive of sepsis in COVID-19
Funder: Diabetes UK

Abstract: Investigating retinal vasculopathy pre-COVID-19 as an independent risk factor predictive of sepsis in COVID-19


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Pre-clinical development of novel oral plasma kallikrein inhibitors for the treatment of diabetic macular edema
Funder: Innovate UK

Abstract: Retinopathy (damage to blood vessels in the retina at the back of the eye) is a serious and common complication of diabetes that can lead to blindness. One of the main problems is that the blood vessels become leaky which allows fluid to escape and accumulate in the retina. There are a limited number of treatment options; laser therapy is commonly used, or alternatively injections into the eye of drugs known to prevent leakiness, although this doesn’t work for every patient. Recently KalVista scientists showed that large amounts of a protein called plasma kallikrein causes the blood vessel leakiness and that a drug which can block plasma kallikrein effectively could become a breakthrough treatment for retinopathy. KalVista is a pharmaceutical company that has extensively studied plasma kallikrein and is proposing to use this experience to develop an oral drug that will block the action of plasma kallikrein which could lead to a brand new treatment for this debilitating and devastating disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: EYE;METABOLIC AND ENDOCRINE