NIHRDataInsights/HRCSData huggingface dataset:
Award Title: MICA: Towards targeted treatment for complex regional pain syndrome through determination of the underlying molecular mechanisms
Funder: Medical Research Council

Abstract: In order to understand the genetic basis for complex regional pain syndrome (CRPS), we recruited two patient cohorts and discovered that four SNPs, each in a different gene, were enriched in CRPS cohorts compared to healthy controls. All four genes are linked to the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. We therefore hypothesise that the SNPs identified cause aberrant activation of NLRP3 to promote the development of the chronic inflammatory pain seen in CRPS. In order to study CRPS, we will initially generate a cellular model by the introduction of each SNP allele into a monocyte cell line THP-1 using CRISPR/Cas9 gene editing (already achieved for one SNP).  Macrophages are highly plastic cells and exist in at least three different states based on environmental cues: naïve M0, pro-inflammatory M1 and anti-inflammatory M2. The transition between M1 and M2 cells is important in wound resolution and healing. We will identify whether the CRPS mutations alter inflammasome activity in macrophages in different activity states by differentiating THP-1 cells harbouring the CRPS SNPs into M0, M1, M2 and M1>M2 states. Inflammasome activity will be determined by measuring pro-inflammatory cytokine secretion (interleukin IL-1B, IL-18) and gasdermin D-driven cell death following activation of NLRP3. These results will be validated in primary macrophages taken from healthy controls with the CRPS-associated SNPs. We will investigate whether the CRPS mutations alter the cross talk between pain and inflammation by measuring the effect of inflammatory mediators released by macrophages on nociceptor sensitisation. We will develop a co-culture system with macrophages and nociceptors differentiated from embryonic stem cells. Nociceptor activity will be measured using electrophysiology. Lastly, we will investigate the effect of inflammasome modulators, provided by NodThera, on the pain and inflammatory responses in the co-culture model.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Award Title: MISFIT – Maximising Inclusiveness in Sports through Female-centric Innovation and Technology
Funder: Innovate UK

Abstract: The needs of older women are largely ignored in many areas of life,?and this is particularly true when it comes to sport and exercise. Yet sustaining fitness and activity levels for women as they age has life-changing and lasting benefits in relation to?physical health,?happiness?and?mental wellbeing.



In the?older female population, a particular barrier to remaining physically active is lower limb pain and injury risks.?Women aged 50+ face particular barriers to getting and/or staying physically active. As well as an increased incidence of pain, discomfort and injury, this group are not well-supported in terms of assistive and appropriate sports technologies, sportswear and footwear -- which tend to be developed for, and marketed to,?young people.?



In fact, the majority of exercise and sport-related injury prevention research is conducted on young, often male, adults, largely in the context of elite sports. The effects of gender and ageing on bodily biomechanics and physiology remain poorly understood, making it challenging to remove or even address these barriers and changes to injury risks. Furthermore, conventional biomechanics studies are limited to laboratory-based research with small participant numbers, preventing large-scale data insights of normal people,?doing normal?sports,?in normal settings. There is an urgent need to progress our understanding of female sports biomechanics through life, and develop relevant technologies and products to support inclusive sports participation by women of all ages.?



Project MISFIT aims to address this gap in the Healthy Ageing space by developing a new movement analytics service that is designed specifically for older women. This will provide?evidence-based?information?regarding?bespoke?exercise regimes?and?injury prevention?to?support continued?safe participation in?physical activity.



MISFIT will build on KYMIRA's?award-winning sports apparel solutions, which will be adapted for older females. The project?uses?smart garments?equipped with sensors and pressure measuring insoles, to capture and integrate kinematic (movement), kinetic (force) and?physiological data during everyday sports.?MISFIT will enable large-scale data-gathering to provide population-level insights into injury mechanisms and optimum exercise regimes as women get older. MISFIT will translate the data and learnings to provide a sports advisory service to users. In a further innovation, award-winning sports footwear developer Ida Sports will use the service to inform the user-centric design of a new range of sports footwear?to support?women?to continue in sport participation?as they age.


Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS
Health Categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE
Award Title: MRC Brain Banks: Joint Application to Underpin Neuroscience Research
Funder: Medical Research Council

Abstract: This joint application from the MRC Brain Banks in Edinburgh, London, Newcastle and Oxford is submitted in accordance with the wishes of the MRC Neuroscience and Mental Health Board (NMHB). After the last funding round for the MRC Brain Banks in 2011, NMHB indicated that a future joint application would be preferred and that the applicants should demonstrate progress in efficiency and improving standards of work in accordance with an agreed set of metrics. This application fulfils this request, and aims to underpin neuroscience research in the UK by providing high-quality human brain tissue samples and data in the formats required by researchers in both academic and industrial settings. The four banks in this application together cover the collection of human tissue samples from a range of major neurological diseases, and normal tissue samples to act as controls. This provides an invaluable resource to underpin neuroscience research in UK, particularly in recently identified priority areas such as dementia. The banks have demonstrated in this application that they can work to the standards set in the metrics agreed with the NMHB, and have improved their efficiency of operations. The banks already support a number of major researchers in academia and industry in UK and overseas, including several who are currently funded by MRC. The provision of high quality tissue samples and accompanying data is essential for the success of these projects; the MRC brain banks constitute a critical infrastructure for this research. In order to develop this important work further, funding for a 5 year period is requested; earlier funding awards for periods of 2 years has not been conducive to long term planning and strategy. The costs of brain banking in the UK compare very favourably with those in Europe and in the USA; over the next 5 years the banks will continue to work to improve efficiency of operation and to operate a cost recovery programme.


Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: NEUROLOGICAL
Award Title: Macrophage driven therapy resistance in AML: from macrophage subset characterisation to the potential for therapeutic intervention
Funder: The Academy of Medical Sciences

Abstract: Acute Myeloid Leukaemia (AML) is a common haematological malignancy in adults, with survival rates less than 20% for the majority of AML patients. Therapy resistance is a major reason for poor survival in adult AML, and is strongly influenced by cells residing within the bone marrow (BM). AML cells interact with immune cells (e.g. monocytes – macrophage precursors) in the BM. Therapy resistance can occur via interactions between leukaemic cells and immune cells present within the BM. CD163+CD206+ macrophages are present in high numbers in the BM of blood cancer patients, including AML and Multiple Myeloma (MM). It is well-established that CD163+CD206+ macrophages promote therapy resistance in MM. However, the contribution of macrophages, towards therapy resistance in AML is poorly understood. This study aims to characterise macrophage subsets from AML patients, and to better understand how distinct macrophage subtypes impact upon therapy response in AML.

Recently, I have shown that leukaemic cell-to-macrophage contact, and secreted factors from CD163+CD206+ macrophages, protect AML cells from therapy-induced apoptosis. Utilising cell and molecular based approaches, the objectives of this research are to: (i) characterise macrophage subsets from AML patients at the molecular and functional level; and (ii) determine the capacity of these macrophages to limit therapeutic efficacy in AML cells. By comprehensively characterising macrophage subsets from AML patients, and ascertaining their impact on therapeutic response, this research will advance our understanding of how macrophages drive AML pathogenesis, instructing future studies aimed at targeting specific Mφs, as a strategy to circumvent therapy resistance in AML.

Lay Abstract: Resistance to cancer therapy is a major reason for treatment failure, disease recurrence and poor survival in acute myeloid leukaemia (AML); a common blood cancer in adults, currently only 1 in 5 patients survive for 5 years or more after diagnosis. AML originates within the bone marrow and communication between cancer cells, and other cells residing within the bone marrow, significantly contributes towards therapy resistance. Immune cells called “macrophages”, are present in high numbers in the bone marrow of blood cancer patients with AML and multiple myeloma; another cancer of the blood. These macrophages are known to contribute towards cancer therapy resistance, through direct physical contact with cancer cells and/or releasing factors that aid in cancer cell survival. It is important that we identify which type of macrophages are capable of driving this therapy resistance in blood cancers, as very little is known about how this occurs. This work will answer a number of questions on how this happens and the research is important in order to explore the potential of new drug treatments for blood cancers.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Magnetic resonance Imaging abnormality Deep learning Identification (MIDI)
Funder: Medical Research Council

Abstract: A clinically validated decision-making tool to identify abnormalities on brain MRI scans does not exist. This project meets this clinical need by developing such an abnormality detection tool using deep learning, enabling immediate automated triage of abnormalities with target product profile diagnostic performance matching that of a consultant neuroradiologist. This is important as 330,000 patients wait >30 days for their MRI reports in the UK. The number is forecast to increase, due to more demand for MRI than the availability of radiologists to report these scans. UK-specific workforce shortages in radiology are negatively impacting patient care by delaying diagnosis; a similar picture is seen globally. Immediate triage of a brain MRI into normal/abnormal allows early intervention to improve short- & long-term clinical outcomes. Furthermore, detecting illnesses early would result in lower costs for the healthcare system given less specialised medicine & fewer hours of treatment are needed for patient recovery. The proposal is enabled by another deep learning labelling tool, allowing MRI scans to be labelled at scale. Our publications confirm that the core approach is not only feasible & effective but also allows subcategorization into relevant groups as secondary objectives. However, there is a technology gap that must be filled to provide a capability ready for a clinical trial. A key objective is to complete analytical validation by 30 months in multiple prospective external test sets. Preparation for Class 2a Medical Device regulatory approval of software & phase III trial design, including a health economic evaluation, will be achieved within 36 months. A trial, beyond the current Award, will complete clinical validation. The commercial exploitation pathway will be developed during the Award prior to the trial where a 3rd party (i.e. commercial partner) will be responsible. IP relates to the software we will generate for the triage tool in the proposal.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: NEUROLOGICAL
Award Title: Manipulating the peripheral nerves of the niche to improve epithelial regeneration of the salivary gland
Funder: Medical Research Council

Abstract: Against a backdrop of an ageing population in the developed world, the impetus to find ways of increasing not only length of life but quality of life is strengthening. In the field of regenerative medicine, significant progress has been made in cell-based therapies, while the manipulation of the stem cell niche to promote tissue regeneration has received less attention. A major component of the niche is peripheral nerves, and there is evidence that peripheral nerves are essential for the development, function and replacement of cells in numerous tissues and furthermore that neuronal signals (such as acetylcholine) are themselves vital within all three of these areas.  I previously demonstrated that replacement of saliva-producing acinar cells by SOX2+ stem cells in the salivary gland is governed by parasympathetic nerves and acetylcholine signalling during homeostasis and following irradiation injury. My hypothesis is that peripheral nerves and/or acetylcholine signalling of the niche can be manipulated to promote epithelial tissue regeneration. To address this question, I will use as a model the salivary gland (SG), which relies on peripheral nerve input and contains defined progenitor cell populations. In addition, quantitative measures of function for the salivary gland are easily obtained (e.g. saliva production), fresh tissue is readily available, and clinically, there exists a significant unmet need to regenerate SGs following diseases such as Sjögren's Syndrome or therapeutic radiation for head and neck cancer.  This project will test the role of the nerves in stem cell transplant in mouse SG and will develop and test locally acting acetylcholine receptor agonists to reactivate resident stem cells. Ultimately, the project will test a novel targeted therapeutic intervention based on manipulating niche signals to promote organ regeneration.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health Categories: NEUROLOGICAL
Award Title: Manipulation of monocytes/macrophages for the control of arthritis pain using pro-resolving lipid mediators and blockade of CX3CR1 receptor
Funder: Versus Arthritis

Abstract: Workstream 3: Development of stratified care for shoulder pain Objective: Integrate results from Workstreams 1&2 to develop a screening and decision tool supporting optimal targeting of shoulder pain treatments. Methods: (a) Semi-structured interviews with approximately 15 patient-clinician dyads to investigate their perceptions of cause and prognosis of shoulder pain, uncertainty and communication around treatment and referral, and opinions regarding the potential of stratified care. Grounded theory and constant comparative method will be used to identify themes, investigating overlaps and contrasts between individuals in the dyad. (b) Nominal Group meetings, involving patients, GPs, physiotherapists, and secondary care specialists. Informed by interview results and evidence from Workstreams 1&2, they will agree: design and format of the tool; matched treatments for defined subgroups; type of training and information materials for clinicians and patients. Key outputs: Evidence-based screening & decision tool with matched treatments for subgroups (stratified care), and supporting materials for clinicians and patients.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Mapping subicular mnemonic circuitry
Funder: Welsh Government Office for Science

Abstract: Memory loss represents a key symptom of dementia and is associated with significant impact on quality of life for its sufferers and, consequently, on society as a whole. With more than 200,000 new cases of dementia expected each year, understanding the neural mechanisms underlying memory processing remains a central, and increasingly urgent, goal of neuroscience.  My project seeks to understand how circuits in the brain encode, store and recall memories for places and events experienced in our everyday lives.  A brain region called the ‘hippocampus’ represents a key brain circuit responsible for memory processing and my work is aimed at understanding how it interacts with other brain areas during learning. In particular, I aim to decode the signals the hippocampus sends out to the wider brain (what is saying), identify the target brain regions for those specific signals (to whom), each during different stages learning (when).  To do this I will study the functional connectivity between the principal output region of the hippocampus (the subiculum) with brain regions known to be important in learning and memory.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Mapping the growing global burden of dengue to help countries plan for the next decade of dengue control
Funder: Medical Research Council

Abstract: Dengue is one of the fastest growing uncontained emerging infectious diseases. Computational models play an important role in estimating disease burden because of the limitations of epidemiological data. This year, new goals for reducing the global burden of dengue between 2021-2030 will be set, but current models are insufficient for tracking progress. In this fellowship I will develop the next generation of global dengue models that take into account the spatio-temporal variation in multiple types of epidemiological data to predict the past, present and future global burden of dengue. A systematic search will assemble incidence and prevalence data at a sub-national level with geospatial models used to make predictions for data deficient areas. A Bayesian multi-serotype dengue transmission model fit to dengue incidence and prevalence data will then give consensus estimates of how dengue burden has changed 2000-2020. These predictions will give insights into how dengue was able to spread so rapidly and help design strategies to contain future arboviral pandemics. With data on >4 million individual-level dengue patient records I will characterise spatio-temporal trends and causal determinants of delayed treatment seeking and misdiagnosis. Using multivariate regression approaches I will then assess the contribution of each of these to the risk of severe disease and death after accounting for relevant confounders. This will give new insights into how to prevent dengue deaths through non-therapeutic approaches. Projecting these models using future climate, urbanisation and immunity scenarios will allow new predictions of future changes in dengue burden. A national feasibility assessment will then rank countries in their ability to meet 2021-2030 goals based on epidemiological, operational and financial barriers. This work can be used to define target product profiles of novel interventions and identify under or over-achieving control programmes.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);1.4 METHODOLOGIES AND MEASUREMENTS
Health Categories: INFECTION
Award Title: Maternal and Perinatal Health Research collaboration, India (MaatHRI): improving outcomes in pregnant women with iron deficiency anaemia
Funder: Medical Research Council

Abstract: India contributes to a sixth of annual maternal deaths globally and over 5 million Indian pregnant women suffer a life-threatening complication. This project aims to establish a UK-India collaborative platform for maternal and perinatal health research (MaatHRI), and use it in the first instance to improve the clinical management and outcomes of pregnant women with iron deficiency anaemia which is a major contributor to maternal deaths in India.  Objective-1 is to establish MaatHRI in 18 hospitals in two states covering ~100,000 deliveries yearly to continue the survey of 6 severe pregnancy complications initiated during the pilot work.  Objective-2 is to investigate the risk factors, clinical characteristics, management and outcomes of anaemic heart failure through an unmatched case-control study using MaatHRI (cases 900 pregnant women with anaemic heart failure; controls 3600 women with anaemia but no heart failure). In-depth review of hospital notes of cases and deaths due to anaemic heart failure will be conducted in each hospital by an expert panel. Lessons identified will be combined with evidence from the case-control study to develop pregnancy care guidance. Objective-3 is to examine the safety of induction and augmentation of labour in pregnant women with anaemia through a cohort study of 10,800 pregnant women with haemoglobin level <10 g/dl using MaatHRI. Results will lead to guidance and interventions to reduce any risk associated with induction and augmentation of labour. Objective-4 is to explore the feasibility of establishing MaatHRI in other states by disseminating the study outputs and mapping potential hospitals through workshops.  Objective-5 is to develop studies on the other surveyed complications and follow-up projects from the outputs. Survey of infectious diseases in India that are emerging risk factors for pregnancy complications will be initiated in year-4 to estimate their prevalence and case fatality, and to develop further studies.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Maximising T cell cytotoxicity and persistence for long term anti-cancer protection in adoptive cell therapy (ACT).
Funder: Wellcome Trust

Abstract: One of the functions of the immune system is to recognise and kill cancerous cells.  This is done by specialised immune cells called cytotoxic T cells.  However, there are many ways in which this process can go wrong, and this leads to the development of cancer.  Many recently developed treatments for cancer are designed to improve the ability of the T cells to recognise and kill the tumour cells, but this is still imperfect and there is lots of room for improvement.  I aim to make alterations to the signals that occur inside T cells after they “see” an abnormal tumour cell, in order to make them more effective at killing cancer cells and to stay around and do this job for longer.  I will test modifications by making relevant alterations to T cells in the lab, and then assessing their ability to kill cancer cells in a petri dish and to destroy tumours in mice with cancer.  Different modifications will enable me to understand how T cells function, and where modifications can be made to improve their tumour killing function.  This could be used in future to modify patients’ own T cells to treat their cancer.


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