NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Development of a system to simultaneously detect mutations and epigenetic marks
Funder: Medical Research Council

Abstract: Changes to epigenetic marks, in particular cytosine methylation, are an key feature of many diseases. For example, it has been shown that CpG-island hypermethylation is a common occurrence in cancer cells. Despite their well-established importance in many diseases, the number of genome-wide maps of DNA modifications is different healthy and diseased tissue types is small. The reason for this is that bisulfite sequencing, the current state-of-the-art method for reading DNA modifications, is more expensive than standard genome sequencing, and requires more material, due to the DNA-damaging nature of chemicals involved. Furthermore, bisulfite sequencing results in a much higher error rate per base. Most projects therefore choose to not perform genome-wide measurements of cytosine methylation. We recently published a new method for sequencing epigenetic marks, called TAPS, that is both cheaper and results in data of very similar quality as standard DNA sequencing. Here, we propose to develop algorithms to identify both genetic variation and epigenetic marks from the same sequencing data simultaneously. This would make it possible to perform only one experiment, at similar cost to standard sequencing, and produce information regarding the genotype and gene regulatory state of a sample at once. We believe that this would greatly increase the utility of the TAPS method, but more importantly it would lead to a more epigenetic information being generated routinely, leading to a much better understanding of the role of epigenetic marks in different diseases.


Research Activity Codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Development of an intervention for improved management of self-reported abnormal vaginal discharge by women in rural north India.
Funder: Medical Research Council

Abstract: Self-reported 'abnormal vaginal discharge' (AVD) is a common clinical symptom of sexually transmitted infections (chlamydia, gonorrhoea or trichomoniasis) or endogenous reproductive tract infections (bacterial vaginosis or candidiasis) and its clinical management is done through the syndromic management approach. This approach was advocated by WHO for low resource settings where laboratory diagnostics is unavailable. However, it is now accepted that AVD (or vaginal discharge syndrome) is neither sensitive nor specific for sexually transmitted infections (STIs), leading to considerable over treatment with antibiotics (up to 65% for gonorrhoea and chlamydia). While more cases of AVD may be attributed to RTIs (bacterial vaginosis and candidiasis) than to STIs, there may be other cultural and psychosocial factors leading to the complaint. In South Asia, a large body of literature suggests that self-reported AVD may be associated with mental health risk factors including stress, social conflict, marital discord, gender disadvantage and poverty. Studies in India and Pakistan have found a strong association between AVD and scores on mental health screening instruments, suggesting a link between AVD and common mental disorders (CMDs). This further confounds the management of AVD in S. Asia.  Our aim is to develop an intervention to overcome the limitations of syndromic management by (1) introducing rapid diagnostic tests to detect and manage BV, TV and CA (2); introducing gold-standard PCR tests for NG,CT for those with sexual risk assessment scores (as PCR tests are comparatively expensive); and (3) adding CMD screening and management to identify high mental health risk individuals and use additional assessment tools for these. The intervention will be implemented in Tehri Garhwal in India, with 20 selected health workers and 40 women seeking care for AVD; a review of the outcomes and a process evaluation will lead to an intervention pilot in the next stage.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;4.3 INFLUENCES AND IMPACT
Health Categories: INFECTION
Award Title: Development of an invertebrate model of alternating hemiplegia of childhood
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Heterozygous mutations in ATP1A3, encoding the Na+,K+-ATPase (NKA) alpha3 subunit, are identified as the cause of a


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Development of inhaled, dual EP2/4 receptor agonists for the treatment of idiopathic pulmonary fibrosis
Funder: Medical Research Council

Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal chronic fibrosing interstitial lung disease with median survival of 3 years. IPF is characterised by formation of fibroblast/myofibroblast foci that excrete excessive extracellular matrix resulting in airway stiffening and loss of pulmonary function. Recent work demonstrated a link between a decrease in prostaglandin E2 (PGE2) signalling and fibrotic disease. Restoration of this pathway via activation of EP2 and EP4 receptors can inhibit, and in some cases reverse, remodelling processes associated with fibrosis. Through an MRC DPFS-funded hit to lead campaign we have identified novel, dual EP2/4 receptor agonists that inhibit fibroblast migration, proliferation and differentiation to a variety of IPF-associated growth factors. We now propose a full Lead Optimisation project to further develop these leads, consisting of chemistry to explore core modification, side chain optimisation and improvement of compound physicochemical properties. As EP2 and EP4 receptors are not restricted to lung we will pursue an inhaled delivery approach to facilitate targeting of compounds directly to their site of action, minimising systemic exposure. We will conduct in vitro characterization against human lung fibroblasts to optimise efficacy against a range of phenotypic responses important in IPF. We will perform detailed pharmacokinetic studies to confirm compound suitability for inhaled delivery. Finally, we will perform pharmacokinetic/pharmacodynamic profiling in the murine bleomycin model to determine efficacy against a chronic pulmonary fibrosis and remodelling response. The ultimate goal is selection of a candidate suitable for progression to GLP long-term inhaled non-human toxicology studies.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: RESPIRATORY
Award Title: Development of rejection-resistant allogeneic chimeric antigen receptor T cells
Funder: Cancer Research UK

Abstract: Chimeric antigen receptor (CAR)-T cells are a breakthrough in cancer treatment, recently approved in advanced B cell malignancies. An important limitation is that CAR-T are currently made as bespoke autologous products, which is expensive, has a 10% failure rate, and a 3-week+ lag-time. In addition, CAR-T quality depends on ‘fitness’ of patient T cells, so is highly variable. A potential solution is batched allogeneic CAR-T (allo-CAR-T) from healthy donors. However, 2 critical obstacles preclude this: graft versus host disease (GvHD) induced by allo-CAR-T, and rejection of allo-CAR-T by the recipient.

GvHD is a potentially fatal syndrome, mediated by T-cell receptors (TCR) of allo-CAR-T, which attack 'foreign' host tissues. To prevent GvHD, investigators have used genome-editing to delete the TCR, a complex approach with risks of genotoxicity. I have developed an alternative allo-CAR-T manufacturing platform without genome-editing. Here, a TCR-specific binder is fused to a Golgi-retention signal (KDEL), and co-expressed with the CAR in one viral vector. TCR-KDEL blocks TCR assembly, enabling TCR-negative CAR-T generation in a single step. This strategy will be tested in a first-in-human MRC-funded phase-1 trial in B cell malignancies (KCAT19), commencing 2021.

However, KCAT19 does not address host rejection of allo-CAR-T. Rejection reduces efficacy by preventing long-term CAR-T engraftment, and occurs by little-explored mechanisms. In this proposal I will examine how allo-CAR-T are rejected, and develop new methodologies to prevent this. My overall aim is to produce truly ‘off-the-shelf’ CAR-T, which do not cause GvHD and persist long-term in patients.

Using samples from patients treated on the KCAT19 trial, I will dissect rejection, investigating the immune cell types and pathways involved in this process, and will correlate clinical results with biological findings.

Simultaneously, I will develop multiple protein-based methods to prevent rejection. One likely major mechanism of rejection is recognition of foreign human leukocyte antigen (HLA) molecules on donor cells by host T cells. Thus, I will test Golgi-retention approaches to HLA, as well as a novel fusion-protein I have developed which simultaneously downregulates TCR and HLA class-1. I will combine these strategies with expression of non-classical HLA to prevent natural killer cell-based rejection. I will engineer allo-CAR-T resistance to pharmacological immunosuppression, enabling use of these drugs to prevent rejection without blocking CAR function. I will test my approaches extensively in vitro and in humanised murine models. The proposal is highly translational, with a genuine prospect of rapid progression to clinical testing during the felowship.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Development of the WESTERN plan for supporting active ageing in retirement and care facilities
Funder: Economic and Social Research Council

Abstract: The main aim of this programme of work is to develop a prototype active ageing intervention and digital platform that engages older adults and fosters the maintenance of physical, cognitive and emotional health and wellbeing. Specifically, by the end of the 12-month funding period, the key outcomes will be:
1. An optimized, evidence-based, package that meets the user needs and is acceptable and effective in meeting its aim of translating care and retirement settings as ones that endorse rather than disavow active ageing.
2. An implementation plan that maps out the steps necessary to appropriately market the WESTERN plan and realize widespread, long-term adoption.

Lay Abstract: This research aims to address the problem of maintaining mobility, wellbeing, and quality of life in older adults in sheltered accommodation, assisted living, care homes and people who require outreach care. In other words, this project will aim to provide a personalized programme that transforms these settings into ones that facilitate rather than impeded active ageing.

Often when individuals reside in such facilities there is a tendency to succumb to an ageing stereotype characterized by a detachment from the wider social community, a reduction in physical activity, apathy towards cooking and eating healthy, balanced meals, and feelings of helplessness. Consequently, age-associated conditions such as cognitive impairment, loss of physical function, frailty and poor mental health are highly prevalent within this population.

Fortunately, many of these issues are preventable (or at the very least, can be decelerated) through simple lifestyle behaviours. Providing a system to motivate, prompt and support older adults to include health-enhancing 'self-care' behaviours into their daily routines can promote active ageing, and curb any preventable mental, physical, and emotional decline.

The WESTERN plan (Walking, Exercise Snacking, Tai-chi, Edification, Relationships, Nutrition) aims to provide a simple, personalized programme that is rooted in behavioural science to optimize motivation, engagement, and acceptability. The plan, which will be provided on a target-user informed digital platform for integration of behaviour change techniques, scalability and dissemination, will provide structure for users, care staff and family members and act as a basis for continued growth, value, belongingness and thriving health and wellbeing in residents.

Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.1 INDIVIDUAL CARE NEEDS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Developmental Assembly of the Serotonin System
Funder: Medical Research Council

Abstract: The serotonin system powerfully modulates physiology and behaviour in health and disease. It is the most widely used pharmacological target for treating depression and anxiety, and depression has become the leading cause of disability worldwide. Despite its functional importance, there are surprisingly few studies that analyse how serotonin neurons are able to reach nearly all neural circuitry with their miniscule cell numbers.  Spectacular progress has been made over the past decades in identifying and understanding how molecular guidance cues work to instruct axon projection. But less attention has been paid to the cellular context in which these cues are produced, presented, and interpreted by growing axons. This could be partially caused by the fact that majority of the axon guidance cues were identified and studied in sensory systems. Although sensory systems provide powerful models for studying synaptic transmission which are restricted to confined brain regions, it is unknown how projections utilize volume transmission find their targets and how they stabilize the connection. The serotonin system is an ideal system to answer this question because it utilizes both wiring and volume transmission, and it is the only neural system that projects to the entire brain. My recent work revealed that the dorsal raphe serotonin system contains parallel sub-systems that have largely complementary whole-brain collateralization patterns and distinct functions. Systematic investigation into the development of the serotonin system can be extremely useful for uncovering new molecular mechanisms underlying neuron-specific development. In addition, it may provide entirely novel targets for therapeutic interventions of psychiatric and other disorders.  We have been applying cutting-edge single-cell mRNA sequencing technology (scRNA-seq) to reveal the transcriptomic identities of mouse midbrain serotonin neurons in both DR and median raphe (MR). Combining these scRNA-seq profiles with viral-genetic tracing results of the projection defined serotonin neurons will allow me to identify the molecular features of each the projection-defined serotonin sub-systems. We shall then build the developmental trajectory for each of the main sub-systems and identify the molecular cues guiding/maintaining the formation of each serotonin sub-circuits during development. We shall validate the candidate genes’ function in serotonin projection wiring specificity in mouse models. Finally, we shall elucidate the relationship between genetic defects of the serotonin system and psychiatrically relevant behaviours in mouse models.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Developmental origins and niches of the haematopoietic system
Funder: Medical Research Council

Abstract: To harness the full therapeutic potential of haematopoietic stem cells (HSCs) and lineage-restricted progenitors to treat blood-related disorders, we aim to better understand their birth in the embryo. Haematopoietic stem and progenitor cells are generated in asynchronous waves from haemogenic endothelium in the yolk sac and the dorsal aorta through a process termed endothelial-to-haematopoietic transition (EHT). EHT is critically dependent on the transcription factor Runx1. In our past work, we have progressed towards fully unravelling the CIS regulatory complexity of Runx1 during EHT and obtained new insights on the timeline and process of early haematopoietic commitment. In our future programme, we will take advantage of new tools we developed and available cutting edge technologies to perform a series of complementary studies that will transform our ability to gain a deep level mechanistic understanding of early blood development. We will combine our unique Runx1 enhancer-reporter transgenic models with chromatin conformation analysis, single cell omics and functional assays to  i) discern the principles of Runx1 regulation during the establishment of haematopoiesis,  ii) deconstruct the HSC-generative niche with the aim to recreate critical components in vitro, and finally,  iii) to elucidate the developmental trajectories of mesoderm contributing to yolk sac and AGM blood cells and their contribution tothe haemato-immune system. Our studies will offer exciting opportunities for translational applications into human models of normal and perturbed developmental haematopoiesis.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: BLOOD;GENERIC HEALTH RELEVANCE
Award Title: DiRECT extension, for a total of 3-years weight-loss maintenance and follow-up
Funder: Diabetes UK

Abstract: Information collected from DiRECT study intervention participants at routine diabetes monitoring suggest that almost half have achieved and maintained a weight loss of 15kg at 12 months. Many are no longer diabetic.

Under the current DiRECT protocol, support for weight-loss maintenance will cease at 2 years.  Evidence from long-term weight management studies show that, without continued support, significant weight regain is very likely.

 Under the planned extension to DiRECT, at their 2 year review appointment intervention participants will be offered continued attending for weight loss maintenance support, every 3 months, for a further 3 years.  Participants will continue to attend their GP surgery for review appointments with the specifically trained Practice Nurse or Dietitian to follow their individually tailored dietary programme for weight-loss maintenance.  People who do not wish to continue will return to usual NHS primary care management.

 Extension of the study will help participants maintain the improvements in weight and diabetes control they have achieved in the initial 2 years of the study, and prolong freedom from diabetes for those that have achieved this for a total of 5 years, more in line with data available after bariatric surgery, which is increasingly required for clinical guidelines.


Research Activity Codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Dietary restriction of micronutrients to slow ageing and treat disease
Funder: Wellcome Trust

Abstract: In biomedical science, there is a growing realisation that the mechanisms of ageing underlie many major debilitating age-related diseases. Interventions in the ageing process therefore have the potential to make an immense impact on our healthspan. The most potent of these interventions is dietary restriction (DR) – decreasing dietary intake but avoiding malnutrition. Translation of DR to humans is impeded by our lack of knowledge on exact mechanisms and the optimal diet. DR is thought to result from a reduced intake of the macronutrient protein. Recent data in from my lab, however, suggests that restriction of micronutrients results in similar benefits to healthspan. I propose that by studying the restriction of micronutrients, translation is facilitated and more specific insight into mechanism is gained, as it provides a more precise intervention. I will elucidate the mechanisms of how dietary micronutrients affect ageing and disease using a systematic and comprehensive research program using the fly. I will screen for micronutrients that improve health and will test specific mechanisms based on my previous work connecting phosphate, copper and mitochondrial oxidative stress. Work in two disease models will complement these approaches, together providing key novel insight into the connections between diet, disease and ageing.

Lay Abstract: Ageing is a major challenge in our society. Many age-related diseases, such as cancer, cardiovascular disease and dementia are thought to share mechanisms fundamental to the ageing process. Interventions into ageing itself therefore have the potential to transform our well-being. The most potent of these interventions is dietary restriction (DR): reducing food intake but avoiding malnutrition. Previous research has suggested intake of protein is responsible for these effects. In my lab I recently found that restriction of micronutrients can have similar effects. I propose that the restriction of micronutrients is easier to apply in humans and will also provide us more information on the underlying mechanisms that could be used to develop drugs. My fellowship will use a comprehensive study in the fruit fly to test the effects of micronutrients on lifespan and disease. These studies will together provide novel insights on how to reap the health benefits of DR.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Differential targeting of the HSV1 vhs endoribonuclease - preferential degradation of cellular transcripts on the endoplasmic reticulum?
Funder: Medical Research Council

Abstract: Herpes simplex virus type 1 (HSV1) virion host shutoff (vhs) protein is an endoribonuclease that specifically targets mRNAs by binding to the translation initiation machinery at the 5' end of the mRNA, but the subtlety of its specificity remains to be delineated. Using RNAseq of infected human fibroblasts we have recently shown that cellular mRNAs exhibit a wide range of susceptibility to vhs activity during HSV1 infection, ranging from no effect to a 1000-fold reduction after 12 hours. Pathway analysis of transcripts reduced by more than 30-fold has revealed a surprising enrichment in pathways related to the extracellular environment, particularly the remodeling of the extracellular matrix.  Furthermore, the most vhs-susceptible transcripts were determined to be enriched in transcripts encoding membrane/secreted proteins in general. This proposal therefore aims to test the novel hypothesis that vhs specifically targets transcripts that are translated on the endoplasmic reticulum (ER), resulting in important alterations to the extracellular environment. The specificity of vhs activity against ER bound transcripts will be delineated using differential expression analysis of total and ER-bound cellular transcriptomes from cells infected with Wt and vhs- viruses. Vhs-induced alterations in the extracellular proteomes will be assessed using tandem mass tagging mass spectrometry of similar infections. Additionally, the vhs interactome will be defined to determine the nature of vhs targeting to specific subsets of mRNAs. Finally, the role of vhs in paving the way for HSV1 glycoprotein translation - the most abundant transcripts present at later times in infection - will be determined. These studies will further our understanding of the molecular consequences of HSV vhs activity within the cell and its impact on the global make-up of the cell, data that will impact on other alphaherpesviruses and viruses in general that encode endoribonucleases.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION