NIHRDataInsights/HRCSData huggingface dataset:
Title: What is the effectiveness of Telemedicine in identifying cases of Diabetic Retinopathy (DR) attending diabetic clinics compared with the usual referral system?
Funder: Wellcome Trust

Abstract: The design is a cluster randomised trial of telemedicine versus usual care in diabetic patients. The primary outcome of the study is the proportion of patients with confirmed DR at Aravind Eye Hospital (AEH). DR will be graded using the International Clinical Diabetic Retinopathy Disease Severity Scale. A sample size of 616 patients in both arms is required to detect a risk ratio of 1.8 or above at 90% power, 1% alpha and a design effect of 2. Eight clinics will be recruited and equally randomized to telemedicine or usual carestratified by distance from AEH. Inclusion criteria include a confirmed diagnosis of diabetes, age over 50, no retinal exam in the previous year. In the telemedicine arm patients will be offered fundus imaging and patients diagnosed with DR or probable DR will be counselled to visit AEH to confirm DR. In the usual care arm, the eligible patients will be counselled and referred to undergo an eye examination at AEH. In both the arms the counselling and the awareness creation materials will be standardised. Fundus imaging will be offered at the end of the study to those who refuse initially and all those in the usual arm who did notattend AEH.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: EYE;METABOLIC AND ENDOCRINE
Title: The role of mitochondria in the aetiology of human quantitative traits and morbidity
Funder: Medical Research Council

Abstract: Mitochondria provide essential multiple functions for the cell. The role of mitochondria in energy production and apoptosis is relatively well understood, but less characterised mitochondrial dynamics such as fusion and fission and mitochondrial-led signalling also play fundamental roles in cell biology. We postulate that one or more mitochondrial molecular pathways contribute to myopia, insulin resistance and susceptibility to atherosclerosis in the general population. Our previous work shows evidence of association between genes that control mitochondrial fusion and fission and the quantitative traits of myopia and insulin resistance. In particular, we hypothesise that increased rates of mitochondrial fusion and fission controlled by nuclear genes are likely to be associated with reduced morbidity, since content exchange between mitochondria is believed to prevent the accumulation of defective mitochondria in the cell by reducing the deleterious impact of individual mitochondrial DNA (mtDNA) mutations and mitochondrial damage. Healthy mitochondria are thought to behave as a super-organelle with continual mitochondrial fusion and fission, controlled by mitochondrial-shaping proteins. However, the mechanism by which the burden of accumulated malfunctioning mitochondria is reduced is unknown. Mitochondrial-shaping proteins encoded by nuclear genes control the process of fusion and fission and the process is observed to be essential for the healthy functioning of mitochondria. By sequencing the mitochondrial-shaping nuclear genes and genotyping mtDNA to assess mutational load, we will test this theory in humans using a population-based cohort measured for these three phenotypes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: EYE;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Retinal vascular calibre - a potential biomarker for early renal and retinal diseases?
Funder: Medical Research Council

Abstract: This project will establish if retinal image analysis can provide novel biomarkers for chronic kidney disease (CKD), diabetic kidney disease or diabetic retinopathy using data from well-characterised prospective population-based and diabetes cohort studies using a two-stage meta-analysis approach on individual participant data. Individuals will be stratified into two groups using measures of renal function (estimated glomerular filtration [eGFR]). The stable kidney function group are individuals in whom eGFR measurements remained >60mL/min/1.73m2 from baseline to 5 year follow-up. Retinal vascular calibre measurements in this "stable" kidney function group will be compared to retinal vascular calibre in individuals with progressive decline in kidney function. This "declining kidney function" group will contain individuals in whom eGFR decreased over 5 years to <60mL/min/1.73m2. Retinal vascular calibre will be correlated with risk of developing progressive CKD or retinal complications (including non-proliferative or proliferative diabetic retinopathy). Estimates of association will be undertaken using logistic regression and meta-analysis approaches independently in each study initially and then combined. This strategy will facilitate potential study-specific design bias and covariates not uniformly defined across studies, which can make evaluation of a combined model difficult. Adjustment for appropriate confounders will be made. This approach will also be evaluated in diabetes cohorts with multiple measurements of kidney function (eGFR; urinary albumin/creatinine ratio) to determine if retinal vascular calibre can identify individuals at increased risk of renal and retinal complications. This research will help determine whether measuring retinal vascular calibre, as part of the NHS diabetic retinopathy screening programme, would offer additional clinical value in identifying patients at highest risk of developing renal failure or sight threatening retinopathy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE;METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: The Northern Ireland Genomic Medicine Centre
Funder: Medical Research Council

Abstract: The overall vision of the NI GeMeC is to bring benefit to patients through improved diagnosis, together with improved understanding of rare diseases and specific cancers by analysing unique prospective sample collections available in NI. By doing so, we will contribute to the development of a UK-wide resource of linked genomic, phenotypic and health record information that would be a key asset driving patient care and directing key research programmes at a local, national and international level. It will harness and enhance existing regional capability in genomic medicine and research, building the capacity of Northern Ireland Health & Social Care (HSC), Universities and Industry to translate research into patient benefits, through active participation in the UK 100,000 Genomes Initiative and beyond.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: EYE;MUSCULOSKELETAL;NEUROLOGICAL;RENAL AND UROGENITAL
Title: Acellular / Smart Materials - 3D Architecture: UK RMP Hub
Funder: Biotechnology and Biological Sciences Research Council

Abstract: In UKRMP2 Acellular we will develop and evaluate new classes of smart biomaterials for application in tissue regenerative therapies in three important clinical areas: eye, liver and musculoskeletal repair. The Hub structure is composed of 4 work packages (WPs) designed to maximise end clinical impact and 3 Strategic Gates as critical checkpoints. In WP1, we will develop a platform of innovative designer materials that enable tissue formation while simultaneously providing biological and biophysical cues for differentiation and hierarchical organisation of well vascularised tissues. The materials development pipeline will be complemented by research into advanced manufacturing strategies to develop 3D tissue engineered porous scaffolds and hierarchical structures. The research will be informed by immunological and safety considerations to enhance the translation potential. Importantly, the specific design parameters for the materials are defined by the clinical need (informed) and outlined in WPs 2-4 which focus on the three clinical exemplars, namely the eye, musculoskeletal repair and the liver. We aim to complete safety and efficacy pre-clinical testing for new biomaterials for cornea and retinal repair, enhancement of cell engraftment in the liver, and for lower limb, shoulder tendon and osteochondral applications. The role of 3 Strategic Gates to ensure the research and pre-clinical work is fully informed by experts in manufacturing, regulatory, immunology and safety considerations. Each strategic gate will be controlled by a group or panel of experts who will meet regularly to discuss the advances and prioritise technologies for clinical translation.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: EYE;MUSCULOSKELETAL;ORAL AND GASTROINTESTINAL
Title: Neural Systems and Circuits for Binocular Vision
Funder: Medical Research Council

Abstract: Design of Studies 1) Parametric assessment of brain's response to binocular depth: this involves collection of brain signals (BOLD fMRI in the case of human studies; electrical activities of nerve cells in the case of animal studies) with simultaneous performance of a behaviourally relevant task. Change of behavioural state will be a parameter in the studies. The human studies will include the investigation of former patient groups. Conservative estimates of required statistical power can be gained from large number of studies conducted with these techniques before. 2) Identification of brain regions processing depth. High-field MRI at 7-Tesla will be used to measure the response of cortical areas and sub-compartments within those areas. Structural and functional measures will be used to gain converging evidence. Technical Measurements 1) High-field MRI at 7-Tesla: BOLD & fMRI, diffusion tensor imaging, multi-voxel pattern analysis, objective identification of cortical areas, visual behaviour within the scanner 2) Multi-electrode neurophysiology in identified locations in experimental animals: statistics of neural firing, correlated firing within populations, identification of "brain signatures" of perceptual events, linking neuronal signals to functional MRI.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;NEUROLOGICAL
Title: A common framework for ambylopic, developmental and adult forms of visual crowding
Funder: Medical Research Council

Abstract: Although it is clear that crowding occurs in three instances of vision - the normal periphery, amblyopic fovea and the developing fovea - it is not known whether these three instances arise from the same mechanism. Our aim is to test whether all three can be commonly understood as a 'compulsory integration' of the visual field, using psychophysics, computational modelling and neuroimaging. There are four research objectives. First, one of the hallmarks of peripheral crowding is that it systematically changes the appearance of objects. We will determine whether this is also true in amblyopic and developmental crowding. By examining what children see under crowded conditions we can develop computational models of the process and compare their operation to models of adult crowding. Second, the key feature of amblyopic crowding is that it is strong in the amblyopic eye and minimal in the fellow eye. Our pilot testing suggests that there are similar interocular differences in regions of the normal periphery. We will measure these 'amblyopic zones' and examine whether 'treatment programs', designed for amblyopia, can reduce these interocular differences in the periphery. Third, we will examine whether crowding in each of the three instances occurs in the same way for the different modalities of vision (e.g. motion vs. colour). Crowding varies in strength across both the visual field and individuals, with amblyopia an extreme case, but it is not known whether these variations are common to all modalities. In measuring this, we will assess whether crowding is a singular process or a more distributed mechanism. Finally, we will directly measure the neural correlates of peripheral and amblyopic crowding using functional neuroimaging. A combination of structural and functional MRI scans will measure the degree of cortical resources devoted to regions of the visual field and relate this to the strength of crowding in both the normal periphery and amblyopia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;NEUROLOGICAL
Title: Deciphering alpha2-chimaerin signalling pathways in ocular motor development and Duane Retraction Syndrome
Funder: Medical Research Council

Abstract: Eye movement disorders are relatively common in humans (~1%). Such disorders include Duane Retraction Syndrome (DRS) a form of squint or strabismus, in which horizontal eye movements are impaired. If the condition is severe, it can lead to weakness of vision and partial blindness, or if less severe, it can be debilitating in daily life. We have previously demonstrated that mutations in the alpha2-chimaerin RacGAP cytoplasmic signalling protein are causal in a congenital form of DRS. Patients with these mutations manifest wiring defects of the ocular motor system - the system of three cranial nerves and six muscles which control eye movements. Our previous work has demonstrated that alpha2-chimaerin plays a key role in integrating axon guidance information and transducing it to remodel the cytoskeleton, allowing precise axon navigation. Manipulation of alpha2-chimaerin signalling in the ocular motor system in vivo produces striking axon guidance defects, akin to DRS in humans. In order to decipher the cellular mechanisms that cause DRS, we require a detailed understanding of the signalling pathways within neurons that involve alpha2-chimaerin. In this project, we will use state-of-the-art unbiassed proteomics approaches to identify novel proteins which interact with alpha2-chimaerin as components of a signalling 'module'. In parallel we will explore the role of previously identified alpha2-chimaerin-interacting proteins. Promising candidates will be validated using subcellular localisation assays and reversed co-immunoprecipitation, and ranked lists of candidates will be refined using bioinformatic tools and databases. Once several key candidates have been identified, their functional role will be tested using in vivo assays for nerve wiring and eye movements in the zebrafish. Our data will be used to generate maps of the protein networks that comprise the alpha2-chimaerin signalling module, and will allow us to determine mechanisms which lead to DRS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;NEUROLOGICAL
Title: Functional genomics identification and characterization of novel disease genes, mechanisms and pathways of ciliogenesis
Funder: Medical Research Council

Abstract: This proposal builds upon our recent results from the first whole-genome reverse genetics screen to identify genes involved in ciliogenesis. This has used high-throughput siRNA-based visual screening, with secondary and validation screens identifying 68 candidate genes. Our proposal integrates existing and new functional genomics data-sets with variant data from existing gene discovery programmes, secondary screens to validate hits, and protein-protein interaction data to confirm that potential ciliary proteins bind to retinitis pigmentosum (RP)-associated spliceosome components. We will then use tertiary screens that include functional annotation with cell biology in physiologically-relevant cell models or zebrafish mutagenesis models. Specific aims are to understand the novel roles of G-protein-coupled receptors (GPCRs) and pre-mRNA processing factors (PRPFs) in ciliogenesis, and how loss of these can lead to neurodevelopmental defects or retinal degeneration, by using stem cell-derived model systems. We will study the role of hit GPCRs in ciliogenesis during neural progenitor differentiation of mouse embryonic stem (ESCs) into neuroepithelial cells and/or radial glial cells. To study the potential ciliary roles of hit PRPFs in a physiologically-relevant tissue, we will use differentiated retinal pigmentary epithelium and photoreceptor-induced cultures derived from induced pluripotent stem cells (iPSCs). Importantly, this approach allows us to study cilia in retinal tissue derived from patients with RP. We aim to demonstrate the clinical utility and validity of an integrated "systems medicine" approach and its ability to make relevant predications about disease causality. The research will complete the functional annotation of genes contributing to ciliogenesis, developing our understanding of the basic biology of primary cilia. It may also identify novel therapeutic strategies to slow disease progression for ciliopathies or RP.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;NEUROLOGICAL
Title: Lipofuscin and the complement system in retinal pigment epithelial cell biology
Funder: Medical Research Council

Abstract: Primary porcine RPE cells will be grown as monolayers in transwells in order to mimic their topography in the retina and permit manipulations at the basal and apical surfaces. Monolayers will be induced to accumulate lipofuscin by being cultured with UV-irradiated photoreceptor outer segments (POS) at the apical side, while being treated with purified complement proteins in the basal chamber. Lipofuscin accumulation within the cells will be quantified by autofluorescence measured with a plate reader or flow cytometry. C5b-9 assembly on the basal cell surface will be measured by immunofluorescence and confocal microscopy. To investigate whether C5b-9 formation on lipofuscin-loaded RPE cells stimulates a pro-inflammatory and/or pro-angiogenic environment as seen in AMD pathogenesis, nuclear translocation of NF-kappaB will be examined using immunofluorescence, inflammasome activation will be analysed by quantifying caspase-1 and IL-1beta and IL-18, zymography will be used to analyse the expression of MMP-2 and -9, and the VEGF-PEDF ratio will be determined via ELISA. We will also investigate RPE properties and functions in a mutant mouse containing a targeted deletion of complement factor H in the RPE, crossed with the ABCA4/RDH8 double KO mouse. The retinal phenotype will be examined by fundus photography, optical coherence tomography, electroretinography and fluorescein angiography (all in the living mouse eye), and post mortem immunostaining of retinal sections and flatmounts to investigate RPE ultrastructure, phagosome maturation, complement activation and lipofuscin accumulation. To characterise tissue histology such as thickness of the outer nuclear layer, hematoxylin and eosin staining will be performed on paraffin-embedded sections. Periodic acid Schiff staining will serve for visualisation of mucopolysaccharides and glycogen, Sudan black will be used to detect lipids, and immunostaining will be used to identify Amyloid-beta. Sections will also be stained for vitronectin, since vitronectin accumulates in subretinal desposits in AMD and may be involved in complement-mediated immune responses. Taken together, this programme of in vitro and in vivo studies will provide new insight into the interplay between the complement system and lipofuscin accumulation in the pathogenesis of AMD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;NEUROLOGICAL
Title: Multi-modal cue integration for auditory spatial location by normal-hearing and hearing-impaired listeners.
Funder: Medical Research Council

Abstract: A faithful perceptual representation of the spatial position of sound sources is fundamental to making sense of the acoustic world. It is required to give a real appearance to the auditory scene, and helps considerably in separating sounds and enhancing listening. But hearing impairment worsens spatial perception, reducing or removing these benefits, and hearing aids can actively interfere with it. The perceptual problem of generating the representation is particularly complicated as there are multiple separate cues to location - not only auditory but also visual and vestibular - yet somehow these are combined seamlessly. Quite how is unclear. The overarching purposes of this programme are therefore to determine (1) how this integration of information, across frequency, time, space and audio or visual modality is done and (2) how it is affected by hearing impairment and aided listening. We will use innovative auditory & audio-visual psychophysical experiments to recreate the real world in the laboratory, emphasizing complex scenes with multiple objects. These will exploit figure-ground separation, so with the same stimuli we can quantify the contribution of spatial cues to both a figure's auditory position and its distinctiveness. We will also exploit front-back indeterminacy to study the effects of vision. Data will be collected using methods such as discrimination of position, subjective reporting of position, and orientation tracking to changes in position. The research will help deliver our long-term aim of developing a fully detailed scientific account of spatial hearing in everyday, noisy listening: i.e., how someone's perception of a sound source's position is determined from the source's actual position in the world. Such a theory will help identify new phenomena which future hearing devices can exploit or mitigate.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE;NEUROLOGICAL
Title: Visual circuit assembly in drosophila
Funder: The Francis Crick Institute

Abstract: Our research has the central aim to uncover the fundamental mechanisms that control the formation of neural circuits using the Drosophila visual system as a genetic model. Photoreceptors (R-cells) in the retina extend axons into the optic lobe consisting of four main areas. R-cells and more than 100 higher-order neuron subtypes closely associate with glial cells and assemble into reiterated columnar and layered synaptic modules with high precision. We seek to elucidate the molecular mechanisms that control the stepwise development of specific neuron and glial cell types from birth to branch formation, and their coordinated interactions. Our current projects focus on the following poorly understood topics: (1) the development of motion-direction sensitive neurons; (2) ganglion- and layer-specific targeting of higher neuron subtypes; intrinsic (3) and extrinsic (4) mechanisms controlling neurite remodeling; (5) positioning and branch morphogenesis of astrocytes; and (6) the role of glia in promoting synaptogenesis. Our studies combine molecular, genetic and advanced imaging techniques to explore these topics with single cell resolution. By analyzing the mechanisms underlying normal brain development we hope at long term to advance our understanding of neurological disorders linked to developmental connectivity defects and neurodegeneration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EYE;NEUROLOGICAL