NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Host determinants of disease outcomes in arboviral infections
Funder: Wellcome Trust

Abstract: Infections of animals or humans by viruses can result in many different clinical outcomes. Studying natural models of infection and disease can help us gain a full understanding of the mechanisms of viral pathogenesis, in the knowledge that this is influenced by virus-host co-evolution. In this proposal, we will study bluetongue, a vector-borne disease caused by bluetongue virus (BTV). Bluetongue is one of the major viral diseases of livestock. Essentially all domestic and wild ruminant are susceptible to BTV infection but the resulting clinical symptoms vary considerably (from mild fever to lethal haemorrhagic fever).
 
 
 
In this proposal, we will address how a pathogenic virus renders some infected hosts seriously ill, whilst causing only mild/no disease in others, despite abundant viral replication in both. We will use in vitro and in vivo experiments to address our overarching hypothesis that the clinical fate of BTV infection is determined by the complex balance between virus replication in the face of the host’s innate and adaptive immune responses. The outcomes of this proposal will inform appropriate control strategies for this veterinary disease and generate an intellectual framework of value in understanding disease susceptibility in many other arboviral diseases of humans and animals.

Lay Abstract: In this proposal, we will study “bluetongue”, one of the most important diseases of livestock, in order to address a fundamental question in infectious diseases: how can a pathogenic virus render some infected hosts seriously ill, whilst causing only mild disease in others, despite abundant viral replication in both?
 
 
 
Bluetongue disease is caused by bluetongue virus (BTV), a virus transmitted to animals by biting midges. BTV can infect essentially all domestic and wild ruminant species, but infection results in variable levels of disease. Sheep are more susceptible to bluetongue disease. On the other hand, goats and cows are more “resilient”, they develop high levels of virus in their blood but rarely show signs of sickness.
 
 
 
We believe that these differences in clinical outcome are caused by events during the early stages of infection when the virus is attempting to replicate within a cell that is urgently mounting an antiviral immune response against the virus. In this project, we will experimentally test this idea. The results will advance our understanding of individual susceptibility to bluetongue disease, inform the design of appropriate control measures and serve as a model to study disease susceptibility in many other viral diseases of humans and animals.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Household clustering of multimorbidity and associations with health and social care need
Funder: Medical Research Council

Abstract: Aim Examine spatial clustering of multimorbidity in individuals, households, and neighbourhoods, and explore how this is associated with health and social care use and mortality. Objectives 1. Complete a systematic review of research examining clustering of multimorbidity and healthcare need within households. 2. Examine spatial clustering of multimorbidity within individuals, households, and neighbourhoods.  3. Examine how household multimorbidity composition and neighbourhood characteristics are associated with health and social care outcomes. 4. Examine the generalisability of findings in a second, large population dataset, exploring how observed associations vary in a different context. Methods 1. Systematic review of literature examining clustering of multimorbidity in households and associations with health and social care utilisation and adverse health outcomes. 2. Cross-sectional observational study using a large population dataset (Lothian DataLoch) to examine spatial distribution of multimorbidity/complex multimorbidity (MM/CMM) in individuals, households and neighbourhoods. 3. Multi-level modelling to examine associations between individual, household and neighbourhood characteristics and health and social care use and mortality. 4. Replication of objective 2 and 3 analysis (Welsh SAIL Databank) to examine generalisability of findings and further explore spatial patterns of multimorbidity in a different social, organisational and geographical context. Scientific and medical outcomes Enhance understanding of how MM/CMM clusters in households and neighbourhoods, and associations with health and social care use and mortality. Application of tools capable of examining multiple levels of complexity will provide a new way of understanding the mechanisms driving multimorbidity and health inequalities, supporting development of strategies to better organise health and social care for people with multimorbidity.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: How do senescent stromal cells subvert the treatment response in acute lymphoblastic leukaemia?
Funder: Medical Research Council

Abstract: Our overarching purpose is to understand better how stromal cells influence and are influenced by cancer cells. We recently identified the development of cancer-associated fibroblasts (CAF) from bone marrow mesenchymal stromal cells (MSC) in acute lymphoblastic leukaemia (ALL). We modelled the de novo development of CAF in vitro from either normal, healthy human MSC or the stromal cell line HS27a upon exposure to ROS-inducing chemotherapy. We could also model their development in vivo, where CAFs formed a nestin-positive niche at which the ALL target cells were 'rescued' from chemotherapy agents upon transfer of mitochondria from the CAF. The CAFs we have identified clearly demonstrate features of senescence which is a tumour suppressor mechanism which is cell-intrinsically activated in the context of cellular stress. We have found that the development of senescence relates not only to chemotherapy exposure but to exposure to certain genetic subtypes of ALL. We hypothesise that senescence of stromal cells plays a role in modulating the differential outcome of treatment in different genetic subtypes of ALL. We aim (1) To characterise senescence development in CAF derived from subtypes representing childhood and adult ALL (2) To characterise the interaction of senescent stromal cells with the different genetic ALL models in murine bone marrow microenvironment. Within the aims, we will probe the system using relevant chemotherapy drugs and commonly-used agents with senolytic capacity,


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: How does SARS CoV-2 infect blood vessels?
Funder: Medical Research Council

Abstract: Vascular symptoms including hypercoagulation are a key feature of severe COVID-19. They have been assumed to arise via infection of endothelial cells, however recent RNAseq analyses revealed that instead it is pericytes - vascular mural cells with intimate connections with endothelial cells and several vital roles in vascular function -  which express the receptor, ACE2, which allows SARS CoV-2 to enter cells. Determining which cells mediate vascular and therefore extrapulmonary organ infection is vital for selecting optimal therapeutic interventions. Through our groups' expertise in vascular biology, virology and clinical haematology, we will identify whether pericytes or endothelial cells are the primary vascular target of SARS CoV-2.  We will utilise a pseudotyped SARS CoV-2 virus (PV), which undergoes a single round of infection and expresses a reporter protein in target cells. We will first compare the efficiency of infection in cultured human pericytes and endothelial cells, before injecting PV into mice and tracking reporter expression across pericytes and endothelial cells of different organs. As SARS CoV-2 does not bind murine ACE2, parallel experiments will test a PV mutated to bind murine ACE2 as well as mice expressing human ACE2. Because increased inflammation and APOE4 genotype both alter vascular permeability and are associated with severe COVID19, we will repeat these experiments in animals with LPS-induced inflammation or that express human ApoE3 or 4. By identifying the cells that first become infected with SARS CoV-2 and the conditions that increase infection, this project will enable proper targeting of therapies to the relevant cells.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: How expectation shapes perception: from cortical layers to brain-wide networks
Funder: Wellcome Trust

Abstract: The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. However, the neural mechanisms by which the brain integrates sensory inputs and expectations, and thereby generates the contents of perception, have yet to be established. I propose that, upon presentation of a predictive cue (e.g., a siren), memory systems pre-activate templates of expected stimuli (an ambulance) in the deep layers of visual cortex, leading to biased processing of sensory inputs from the very moment they arrive. Such biased processing then leads naturally to biases in perception, in extreme cases even hallucinations.   I will test this proposal by addressing three complimentary questions: 1) How do the neural computations underlying perception unfold over time? 2) What is the fundamental computational architecture of visual cortex? 3) What is the neural source of expectations? I will combine psychophysical tasks probing participants’ perception with neuroimaging tools with exquisite temporal (MEG) and spatial (high-field fMRI) resolution to address these questions.   The overarching aim of my research is to provide a mechanistic account of subjective perception. Ultimately, these insights may improve our understanding of clinical disorders characterised by aberrations in perception, such as psychosis.

Lay Abstract: The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. For instance, when driving in a rainstorm, our prior knowledge about streets leads us to perceive horizontal, fast-moving blurs as cars, and vertical, slow-moving shapes as pedestrians, even if the blurry shapes themselves are ambiguous. Despite all of us experiencing this remarkable phenomenology, the brain mechanisms underlying it are largely unknown.  I will conduct brain-imaging experiments aimed at addressing this question. I will give people tasks that reveal influences of prior expectations on perception, while using brain-imaging technologies to pinpoint the ongoing neural computations in memory and visual systems. The ultimate goal of my research is to understand the mechanisms by which the brain generates perception. These insights may improve our understanding of clinical disorders like psychosis, which are characterised by aberrations in perception, such as hallucinations.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Human rhinovirus VP4: membrane pore-forming capsid protein and conserved target for broadly neutralising antibodies
Funder: Medical Research Council

Abstract: The picornavirus capsid comprises sixty copies of each of VP1, VP2, VP3 (which form the icosahedral non-enveloped particle) and VP4 which is a small, myristoylated internal protein which stabilises the capsid structure. During cell entry, VP4 is irreversibly externalised and interacts with membranes to form a multimeric pore thought to be involved in delivery of the RNA genome into the cell. In this project we will use virus particles, VP4 peptides, liposome model membranes and biochemical and structural approaches to gain fundamental understanding of how VP4 multimerises and inserts in the membrane and how VP4 emerges from the HRV capsid.  The capsid is dynamic and undergoes a process of 'breathing' whereby internal components such as the N-terminus of VP4 are transiently exposed at the capsid surface. Antibodies raised against N-terminal VP4 peptides can recognise VP4 and neutralise the virus. The N-terminus of VP4 is highly conserved and existing evidence from studies with HRV and related picornaviruses strongly suggests that antibodies against VP4 are highly likely to be broadly neutralising. We will define protective epitopes in VP4 and present them in an immunogenic form to induce antibodies that react with the emerging N-terminus of VP4, neutralise the virus and protect against infection in an established murine model for HRV infection.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Hydrotherapy
Funder: Duchenne UK

Abstract: The quality of life in young males with DMD is negatively impacted by daily pain, changes in body composition and a lack of support to undertake physical activity. Hydrotherapy represents a potential means of involving boys and adolescents with DMD in activity that could benefit the negative factors influencing their quality of life. This project has 2 goals: 1)to allocate a clinical physiotherapist to a project implementing hydrotherapy in young males with DMD to establish whether there are meaningful benefits to their daily life. 2)to conduct patient and parent interviews to understand the barriers to completing a hydrotherapy intervention and ensure our future research addresses meaningful outcomes for those with DMD.


Research Activity Codes: 6.7 PHYSICAL
Health Categories: MUSCULOSKELETAL;CONGENITAL DISORDERS
Award Title: ICR Stratified Medicine Technology Hub: SMP2 - Costed Extension
Funder: Cancer Research UK

Abstract: The CRUK-SMP2 is undertaking the large volume national molecular pre-screening which integrates with the National Lung Matrix Trial. There is a testing platform using Illumina's technology to query 28 different genes for mutations, copy number alterations and translocations. The pre-clinical justification for each biomarker–drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Patients carrying specific DNA alterations are recruited to one of the 18 different cohorts.


Research Activity Codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: CANCER AND NEOPLASMS
Award Title: IDDO: FAIR, equitable and sustainable data platform for infectious diseases
Funder: Wellcome Trust

Abstract: The COVID-19 pandemic has once again exposed the lack of coordination and cooperation across the research and development efforts of the infectious disease community. A key indicator of this failing is the lack of international, interoperable data platforms to provide rapid insight into disease pathogenesis and treatment. Access to data is an important tool for accelerating evidence, product development, and scientific innovation. Enhanced technology, infrastructure and systems for data platforms will increase Findability, Accessibility, Interoperability, and Reuse (FAIR), so that science can advance in a rapid, robust and innovative way, saving lives in the affected communities. Recognising the importance and complexity of the task at hand, this project brings together the vast experience of IDDO, Vivli, and other key stakeholders to deliver a broad, effective, and sustainable data platform(s) for infectious diseases. In this project, IDDO will:   • Enhance its platform for improved findability, discovery, and persistence which ensures that data are available in the long-term;  • Optimise and accelerate its data curation capacity;  • Streamline and accelerate its data access workflow;  • Develop a business plan to secure the sustainability and success of the platform


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: INFECTION
Award Title: IL13RA2-targeted T-cell therapy for paediatric high-grade gliomas
Funder: LifeArc

Abstract: High-grade gliomas (HGG), referred to as Diffuse Midline Gliomas (DMG), are childhood central nervous system tumours that are very difficult to treat. DMG is the second most common type of primary, high grade brain tumour in children and, sadly, fewer than 10% of children live more than two years after diagnosis.

With this project, Dr Karin Straathof’s team is developing a type of immunotherapy for DMG using immune cells called T cells. T-cells play a vital role in our immune system, recognising and eliminating cells infected with, for example, a virus. However, unlike infected cells, cancer cells often go unnoticed by T cells as they appear similar to the healthy cells from which the cancer has developed. To get around this, and use the power of T cells as cancer therapy, T cells can be engineered to recognise cancer cells using an artificial receptor called a chimeric antigen receptor, or CAR for short.

Early results with CAR T-cell therapy for adults with high-grade gliomas show that these engineered T-cells can attack the tumour. However, the responses are variable and relatively short-lived. This is probably because tumours such as DMG create an environment in which the CAR-T cells can only work for a short period of time. Therefore, in this project, patient T cells will not only be engineered with a CAR which enables the T cells to recognise the tumour, but also with other modules which provide the T cells with extra ‘powers’ to continue to work despite barriers put up by the tumour to avoid CAR-T cell attack.

The team aims to develop a CAR T-cell that responds specifically to a membrane protein, IL-13RA2, which most paediatric HGGs express.

In addition, the team aims to:

engineer the CAR T-cells with functional modules to overcome challenges at the tumour site
test different modules using relevant pre-clinical models
select the most promising approach to translate into a clinical study.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health Categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Award Title: IMPRESSeD: IMproving facial PRosthesis construction with contactlESs Scanning and Digital workflow.
Funder: Leeds Hospitals Charity

Abstract: The funding is supporting a 3 year fellowship project that aims to improve the way we make facial prostheses for patients with facial defects by using digital technology.

Lay Abstract: The funding is supporting a 3 year fellowship project that aims to improve the way we make facial prostheses for patients with facial defects by using digital technology. The are four key stages to the fellowship:
• Stage 1 has been completed and has reviewed past research to find out how other researchers have measured the success, costs and benefits of making facial prostheses.
• Stage 2 is nearing completion and has been testing different workflows for making facial prostheses to see how accurately we can design and make facial prostheses using computers.
• Stage 3 is a small trial that will provide evidence to support a larger trial that will compare patient preference, costs and benefits of making prostheses by hand or using digital technology. This initial trial has recently started at Leeds Teaching Hospitals NHS Trust and will be starting at Guy’s and St Thomas’ NHS Foundation Trust in the coming weeks.  
• Stage 4 is being undertaken alongside the other stages of project and will consider whether there is enough evidence to use the digital technology in the NHS or whether larger studies are required.

Research Activity Codes: 5.3 MEDICAL DEVICES
Health Categories: ORAL AND GASTROINTESTINAL;MUSCULOSKELETAL
Award Title: IMmunity Profiling of pAtients with Covid-19 for Therapy and Triage (IMPACTT)
Funder: Innovate UK

Abstract: The IMPACTT project will study the immune profiles of 3,000 patients infected with SARS-CoV-2 in order to understand our immune responses to the virus.



This project will generate five outputs:



1\. Generation of a panel of immune related biomarkers that are predictive of response to treatment, including adverse events



2\. Understanding why some patients have very mild symptoms, yet others have severe reactions that result in ventilation and even loss of life;



3\. Identification of novel therapeutic targets;



4\. Publicly available database of the immune profiles of 3,000 patients;



5\. Creation of a biorepository of 3,000 patient samples to support further research into the SARS-CoV-2 virus.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: INCAR: Innovative CAR Therapy Platforms
Funder: Cancer Research UK

Abstract: Background
The Innovative CAR Therapy Platform (INCAR) initiative aims to launch a consortium of European centres to support in-depth research into Chimeric Antigen Receptor (CAR) engineered cellular therapies. INCAR brings together world-class centres (University of Milan-Bicocca, Ospedale Pediatrico Bambino Gesù, ASST Papa Giovanni XXIII, Cancer Research Center FICUS, and University College London) with established programmes in CAR therapies for a range of malignancies, and with a number of phase I/II studies either open or in implementation. The goal of the consortium is to improve patient outcomes and broaden applicability of T-cell therapies by dissecting biological factors influencing CAR T-cell mechanisms of action.

Aims
Uniquely possible within a collaborative academic network, the consortium will take advantage of differences in cellular platforms, CAR design, manufacturing and gene transfer methods to dissect key biological factors which influence the mechanism of action of CAR-engineered cellular therapies. We anticipate this approach will rapidly enhance our understanding of mechanisms responsible for efficacy and toxicity as well as catalyse further research in the field.

 Method
The proposed goal will be achieved through the complementary approaches of the participating teams in terms of clinical and academic expertise, skills and techniques, as well as of the core facilities underpinning the host institutions. The project will capitalize on development of novel automated manufacturing platforms and preclinical systems to investigate potency and toxicity. Furthermore, CAR T-cell interactions with their microenvironment and the biological determinants of T-cell potency will be unraveled through transcriptional analysis and Next-generation flow-based immune monitoring. Emphasis will be placed on a collaborative scientific approach, establishing standardized protocols, constructive data-sharing and rigorous output assessment, to ensure progress is rapidly achieved. A project management team will schedule collaborative meetings to maximize outputs and a patient’s association will play an integral part in the Consortium’s steering committee.

 How the results of this research will be used
Identification of factors contributing to T-cell fitness, genotoxicity mediated through CAR T-cell manufacture and dissection of the role of the microenvironment in CAR T-cell responses will be disseminated through the consortium
to stimulate further academic investigation as well as development of novel optimised manufacturing methods, standardised release criteria, immune monitoring tools and recommendations to accelerate progress in CAR T-cell immunotherapy. We believe this is a unique opportunity to exploit differences in delivery of CAR T-cell therapies to better understand these highly innovative therapies and catalyze further breakthroughs in the treatment of cancer.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS