NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Rethinking Wellbeing: Evaluating the Neoliberalisation of Wellbeing in the Workplace Using Artworks as a Critical Lens
Funder: The British Academy

Abstract: Workplace wellbeing programmes have increasingly become a central part of work and organisational life within a neoliberal economy, offering solutions to stressful working environments and the challenge of maintaining good physical and mental health. Yet how is wellbeing to be appraised when organisational austerity measures and modern efficient management approaches lead to a lack of wellbeing? This confuses the centrality of the idea of wellbeing as something critical to life with ‘wellbeing’ as an imposed
free-market enterprise motivated by profit and productivity. By examining how contemporary artists critique the obsession with performance and quantification within neoliberal organisations, this interdisciplinary project will assess this confusion in a new way. It will evaluate how different aspects of neoliberalism have appropriated wellbeing, by demonstrating how art adds a much needed complexity to the debate around Positive Psychology and self-optimisation in the workplace.


Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE;MENTAL HEALTH
Award Title: Retinoic acid metabolism blocking agents (RAMBAs) to treat hand osteoarthritis
Funder: Medical Research Council

Abstract: Pathogenesis of osteoarthritis (OA) remains poorly understood, but there is a general consensus that mechanical load and inflammatory signalling drives tissue catabolism. Hand OA has strong genetic heritability. A recent GWAS identified common polymorphic variants in ALDH1A2 in individuals with severe hand OA. ALDH1A2 codes for the enzyme that is responsible for synthesising retinoic acid. We have shown experimentally that retinoic acid levels drop dramatically in response to mechanical injury of cartilage and maintaining levels of retinoic acid in the chondrocyte at the time of injury with talarozole, a retinoic acid metabolism blocking agent (RAMBA), prevents the up-regulation of injury-driven inflammatory response genes. We have also confirmed this reciprocal relationship in patient tissues by showing that the articular cartilage (removed at time of hand surgery) of individuals homozygous for the high-risk variants had significantly lower levels of ALDH1A2 mRNA and other retinoic acid-dependent genes, whereas key inflammatory genes were increased in these individuals.  In this project we hypothesise that talarozole, by blocking breakdown of retinoic acid, will enhance retinoic acid-responsive genes and suppress OA chondrocyte inflammatory genes in hand OA. We will conduct a randomised, placebo controlled study of talarozole in 44 patients immediately prior to planned surgery for base of thumb OA. Primary outcome will be mRNA levels for a panel of retinoic acid and inflammatory response genes. This study will (i) provide evidence as to whether systemic administration of this class of drug is able to penetrate the joint and modify the retinoic acid pathway in human chondrocytes in vivo; (ii) establish whether augmenting retinoic acid can suppress chondrocyte inflammatory gene regulation in hand OA as a pre-requisite for suppressing pain and degeneration; (iii) provide preliminary data that will be used to design a full clinical trial of a RAMBA in hand OA.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL
Award Title: Rivaroxaban versus warfarin for stroke patients with antiphospholipid syndrome, with or without SLE (RISAPS): a randomised, controlled, phase II/III, non-inferiority trial
Funder: Versus Arthritis

Abstract: Thrombotic antiphospholipid syndrome (APS), a serious and potentially fatal complication of systemic lupus erythematosus (SLE), is a recognised cause of ischaemic stroke or progressive cognitive impairment, in part due to recurrent cerebral infarction or progression of cerebral white matter hyperintensities (WMH) of presumed vascular origin, on magnetic resonance imaging (MRI). Prevention of stroke is an NHS priority. The current mainstay of the treatment of thrombotic APS is anticoagulation with warfarin, which has many limitations. We propose a phase II/III randomised controlled trial of rivaroxaban in APS stroke patients, with or without SLE, to assess the efficacy of rivaroxaban for the secondary prevention of stroke in these patients. The primary outcome measure will be the rate of change in brain WMH volume on MRI, a surrogate marker of brain vascular tissue damage, as recurrent strokes in APS patients are rare because of effective anticoagulation. Other brain MRI biomarkers, clinical efficacy (thrombotic events), safety (serious adverse events and all bleeding events), the rate of change in cognitive function and quality of life will also be assessed. In addition a Health Economic evaluation will be undertaken. This study should enable identification of the optimal anticoagulation in stroke patients with APS/SLE and thus improved patient care.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Robotics to enhance independence & safety for dementia patients in the home
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK.  Funding details for UK DRI programmes will be added from 2020. Interactive ‘social’ robots have laboratory established capacity used to engage and stimulate people living with dementia. They can: (a) undertake diverse behaviours; (b) collect rich data; (c) change the environment and (d) respond appropriately in a flexible, task-dependent manner. They provide a way to continuously monitor the home and engage with people to support behaviour or to provide companionship. However, their clinical potential is untapped and development of robotics for dementia care is at an early stage. We will develop an automated ‘family’ of robotic devices focusing on improving safety in the home and enhancing the quality of life for a person living with dementia. The robotic devices will be designed to be safe, accessible and enjoyable to engage with. A design sprint will be used to define key features and functionality. The team will develop a small number of exemplars providing proof-of-principle. For example, they will develop robotic systems to respond to (a) environmental alerts produced by the Healthy Home (e.g. noting a kitchen spillage or cooker left on); and (b) alerts related to the person with dementia (e.g. responding to signs of agitation or injury). Following an alert, the robot device will engage with the individuals and, guided by information from a smart environment, will act to reduce risks. The simplest solution may be to direct the owner (help to clean a spillage), but it may be possible to deploy automated tools to achieve similar ends. In the case of agitation, for example,, if a cause can be identified such as confusion simple interventions may be effective and interactions through a conversational agent or social robot may be directly beneficial. A related focus for the programme will be to develop effective methods of communication between people with dementia and robotic devices. The design process will evaluate the impact of variations in features such as configurable visual appearance, voice characteristics, movement, and tactile features that are optimal for the individuals involved, and the team will produce ‘lightweight’ prototypes for testing purposes.). Main objectives include 1. To produce robotic devices with elementary AI that are capable of interacting with people living with dementia. 2. To integrate robotic devices within smart living environments to monitor and manage the environment for improved safety and quality of life. 3. Draw from user-centred design to define the characteristics of robotic devices suitable for these tasks


Research Activity Codes: 5.3 MEDICAL DEVICES
Health Categories: NEUROLOGICAL
Award Title: Role and regulation of cyclin F in the cellular responses to ionizing radiation (IR).
Funder: Medical Research Council

Abstract: A feature of cells exposed to IR is the activation of a G2/M checkpoint, which controls cell cycle progression, allows damage repair or drives cell death. From work in my laboratory, cyclin F has emerged as a crucial regulator of multiple aspects of the G2 phase (D’Angiolella et al., Trends in Cell Biol, 2013). I found that cyclin F act as an E3 ubiquitin ligase and induces the ubiquitin-mediated proteolysis of the Ribonucleotide Reductase subunit (RRM2) (D’Angiolella et al., Cell, 2012), which controls production of dNTPs, the building blocks of DNA. After the induction of the G2/M checkpoint by IR, cyclin F is proteolyzed to allow production of dNTPs for DNA repair and to modulate multiple aspects of the IR response. How cyclin F activity and levels are regulated by the checkpoint, however, is not understood. We have identified discrete phosphorylation events on cyclin F, which change dynamically upon checkpoint induction and we have shown that cyclin F is phosphorylated directly by cyclin-dependent kinases, Wee1 and Chk1. Furthermore, we have identified the E3 ubiquitin ligase βtrcp as an interacting partner and regulator of cyclin F. We will establish how cyclin F activity and levels are controlled during the checkpoint induced by IR and the impact on the production of dNTPs (Aim1). These studies will reveal how DNA replication and checkpoint responses induced by IR in S and G2 phases of the cell cycle are coordinated with dNTP production. Since altered cyclin F levels have been described in hepatocellular carcinoma and ovarian cancer, where cyclin F levels correlate with survival outcome (Carlucci, D’Angiolella, Br J Cancer, 2015), our studies may also predict patient responses to IR and checkpoint inhibitors in the presence of altered cyclin F levels. In addition to RRM2, preliminary studies from my laboratory have identified Scaper as an additional substrate of Cyclin F. Scaper is a poorly characterized regulator of cell cycle progression that regulates cyclin A localization (Tsang et al., J Cell Biol, 2007). We have observed that Scaper has a crucial role in regulating cell survival after IR. We propose to further investigate the role of Scaper and its regulation by ubiquitin mediated proteolysis mediated by cyclin F and APC/C (Aim2). Interestingly, deletion and mutations of Scaper are frequent in cancer cell lines and tumors. Our studies may predict patient responses to IR and checkpoint inhibitors in cancers bearing Scaper mutations.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Role of NFAT in the vascular endothelium
Funder: Medical Research Council

Abstract: Calcineurin-NFAT signaling plays a crucial role in the regulation of many cellular processes. In the immune system, where it is particularly well studied, it plays a key role in the transcriptional regulation of many cytokines, chemokines and growth factors. However, the role of this pathway in the vasculature is still not fully delineated, although it has been implicated in the maturation of coronary valves and lymphatic vessels. We recently re-examined the consequences of loss of NFAT signaling in the endothelium. This revealed a previously undetected defect in venous development in these mice. Although vein endothelial cells are molecularly and functionally distinct from their arterial and lymphatic counterparts, the signalling and transcriptional pathways controlling of venous differentiation are not well characterized. Analysis of publicly available NFATc1 ChIP-seq data in vein endothelial cells demonstrated direct NFATc1 binding to enhancer regions of numerous key venous differentiation genes, suggesting that NFAT factors may directly regulation venous identity. In the project, we will use a combination of mutational analysis and enhancer characterization in zebrafish, mouse and in vitro models to determine the exact role of calcineurin-NFAT signaling in venous development, identify the direct target and partner proteins of NFATs factors, and establish the upstream regulators controlling vein-specific expression of this transcription factor family.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: CARDIOVASCULAR
Award Title: Role of glycolysis in mesoderm specification and self-organisation of the anterior posterior axis in the mouse embryo.
Funder: Medical Research Council

Abstract: As organs and organisms develop and grow, two cellular processes must be tightly coordinated. In the first, cells must undergo a series of cell specification events to generate the complete array of required cell types.  Secondly, progenitor populations must grow and proliferate at the correct rate to generate well-proportioned organs and tissues. Understanding the control mechanism that links growth and differentiation is both essential for a full appreciation of the underlying mechanisms of embryonic development and for the understanding how these cellular behaviours become uncoupled in the transition from homeostasis to cancer pathogenesis. This proposal aims to investigate the molecular mechanisms that lay at the interface between these two processes, as the early mesoderm is specified and expanded during early gastrulation. Given glucose is the most commonly used carbon source for energy production and biosynthetic pathways, we hypothesise that glucose uptake and metabolism is a central component in linking specification and growth during mammalian gastrulation. To test this, we will use and experimental system that enables the alteration of nutrient supply and metabolism in a controlled manner.  During the course of development, a pole of mesodermal cells forms and break the symmetry setting up the anterior-posterior axis in gastruloids. We will first determine how glucose import is regulated by the differential expression glucose transporters. Next, we will determine the importance of glucose uptake in growth and specification of early mesoderm. Finally, we will implement state-of-the-art metabolic flux analysis to determine how glucose is metabolised through different biosynthetic pathways. Ultimately, this work will provide improve our ability to manipulate cell types metabolically to obtain specific cell types in vitro for further applications such as regenerative medicine.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Role of median eminence oligodendrocytes in the development of obesity
Funder: Wellcome Trust

Abstract: One’s appetite and body weight are primarily controlled by neurons in a brain region called the hypothalamus, which respond to signals from the organs involved in digestion and metabolism. These signals reach the hypothalamus after being transported through another brain reigon, the median eminence (ME). New evidence suggests that non-neuronal cells, called oligodendrocytes (OL), may contribute to the ME’s control of signal entry to the hypothalamus; OLs intentionally die and are replaced throughout adult life and express receptors for peripheral signals, both behaviours which change based on nutritional status (i.e. when one last ate) and coincide with changes in permeability of the ME.We aim to determine how obesity disrupts the function of OLs in the ME, and how this may alter ME permeability. We will block certain functions of OLs in obese mice and identify the physiological consequences, identifying genes involved in these processes. We will use this data to identify candidate mechanisms which may alter OL function and influence healthy physiology. We will also explore the possibility that a new class of obesity drug, which mimic the signalling of hormones naturally released in the body, have their therapeutic effect by targeting OLs and changing ME permeability.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Role(s) of Fibrillin-1 in post-traumatic osteoarthritis
Funder: Versus Arthritis

Abstract: Fibrillin-1 is a glycoprotein found in the pericellular matrix of articular cartilage (AC). My studies so far have shown that Fibrillin-1 is lost with osteoarthritis in a spontaneous (Str/ort) and a trauma-induced model of osteoarthritis, as well as in human OA cartilage. In addition, I have now found that abnormal Fibrillin-1, as found in Tight Skin mice, leads to increased OA severity, in particular affecting non-cartilage tissues (ligaments and synovium).
The aim of this award is to determine the role of Fibrillin-1 in OA development and potential novel mechanisms involved in joint degeneration.
To achieve this, over the next 8 months, I will use transgenic mouse lines with Fibrillin-1 deletion in the whole limb, or in articular cartilage alone, and measure their OA severity in response to trauma (using a non-invasive model of PTOA that I have pioneered). In addition, I will be testing which cell signalling pathways are involved in these effects, in particular integrin activation. This is based on previous work on Fibrillin-1 in non-skeletal tissues. 
This project will determine the role of Fibrillin-1 in musculoskeletal tissues, in particular in response to mechanical trauma, and whether its downstream signalling are viable targets for therapy against OA.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MUSCULOSKELETAL
Award Title: SAFEguarding children in Substance exPosed fAmilies by supporting the non-using CaregivEr: Safe Space
Funder: Medical Research Council

Abstract: Parental substance misuse is a substantial public health and safeguarding issue. Research in this area typically focuses upon developing and evaluating interventions to reduce substance misuse in the misusing parent. The presence of a non-substance misusing parent/caregiver has been found to offer some protection from harm to children in substance exposed families. Despite this, there is a lack of research examining interventions to support the non-substance misusing parent/caregiver to achieve health and well-being outcomes for themselves and their children.  Our project aims to develop an intervention for this population. Our specific objectives are: - To understand the real world formal and informal structural, social and individual level systems of care and the impact of these as barriers and facilitators to effective health and social care for dependent age children and families affected by parental substance misuse - To examine the knowledge, skill and support needs of non-substance misusing parents/caregivers of dependent age children affected by parental substance misuse - To co-produce an intervention for non-substance misusing parents which seeks to support them and their children. The methods we will use to achieve our objectives: - Soft-systems methodology to map out the wide range of formal systems and co-construct social reality maps which capture details of health and social care provision for families affected by parental substance misuse - Social Network Analysis to explore the formal and informal care networks accessed by children in substance exposed families and the non-substance using parents/caregivers - In-depth qualitative interviews with non-using parents/caregivers to identify which causal or contextual factors increase the likelihood of harm to the family and which have the greatest scope for change as well as the mechanisms of change - Co-production workshops with practitioners and non-substance misusing parents/caregivers.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: MENTAL HEALTH
Award Title: SARS-CoV-2 immunoepidemiology in Wellcome-funded urban and rural cohorts in Malawi : generating evidence to inform regional medium and long term decision making
Funder: Wellcome Trust

Abstract: General population serosurveillance in low-income Africa is fundamental to understanding the population exposure to SARS-CoV-2, to explain the observed epidemiology and to ensure that ongoing control measures in the region are proportionate and are not guided by observations from very different settings. Detailed longitudinal immunological studies of infected individuals will be key to determining the long-term strategy in managing COVID-19 in highly vulnerable African populations.
 
Utilising the longitudinal urban and rural cohorts established by the Malawi Epidemiology and Intervention Research Unit, and supported by international and national expertise, we will undertake population immunoepidemiological surveillance to understand the trends in exposure and transmission of SARS-CoV-2, risk factors for SARS-CoV-2 infection and severe disease, as well as the proportion of asymptomatic or pauci-symptomatic infection in the population to enable an accurate estimate of infection fatality rate. Furthermore, we will recruit individuals with evidence of past SARS-CoV-2 infection to a nested cohort with 3-monthly sampling, to explore the magnitude and duration of antibody response and protective immunity in the Malawian population, and at the same time creating a biorepository for further in-depth virological and immunological studies.


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: INFECTION
Award Title: SE0567: Coronavirus Susceptibility of Deer in Great Britain
Funder: Department for Environment, Food and Rural Affairs

Abstract: Deer species are variably susceptible to beta-coronavirus infections including SARS-CoV-2, bovine and bovine-like coronaviruses (BoCoVs).  Some are zoonotic/reverse zoonotic (e.g. SARS-CoV-2, HuCoV-OC3 of rodent/bovine origin) others cause infection of wild and domestic ruminant’s including deer.  Deer species, including those in GB, are known to express the cellular receptor (ACE2) for SARS-CoV-2 indicating possible susceptibility to infection at a cellular level. Our understanding of the role of CoV hazards, threats and risks with respect to wildlife, livestock and humans


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION