NIHRDataInsights/HRCSData huggingface dataset:
Title: GPARTS - Daniel Butler
Funder: Public Health Agency, NI

Abstract: Project/Research Title. How can inclusion health be developed at the ‘Deep End’ of Northern Irish General Practice. Project Summary/Abstract. Those who live in deprived areas experience worse health outcomes [1], as seen by Covid-19 morbidity and mortality data[2]. General Practitioners (GPs) working in these areas experience increased workload, higher demand, shorter consultations, more stress and burnout[3-6]. Funding traditionally has not helped fully address this mismatch of need versus available resource[7]. The main research question aims to investigate the Northern Ireland specific problems faced in General Practice at the ‘Deep End’ of deprivation. To do this, GPs working in these areas, will be approached to form a working group aiming to identity problem areas and find possible solutions to these, publishing the findings as a report to help unify, clarify and advocate for ‘Deep End’ General Practice at a wider policy level. The first steps have been identifying General Practices working in areas of significant deprivation, using the data from the Northern Ireland Multiple Deprivation Measures 2017 and practice lists. Identifying 44 practices with >50% of the patient population living in postcodes within the lowest quintile of deprivation. The next steps are getting the support of leaders and organisations within General Practice, before exploring the key personal and public involvement (PPI) factors around this project, prior to approaching individual clinicians in the autumn of 2021. Research Objectives: To address the question: what are the service development priorities for General Practice at the Deep End? Investigating the key issues faced by healthcare workers in areas of deprivation and possible solutions to these. To review educational and training opportunities in areas of deprivation within Northern Ireland as a way of addressing the workforce issues in these areas. Design and Methodology. Mixed methods, initially quantitative approach looking at defining the areas affected by blanket deprivation in Northern Ireland and the educational and training implications. This will be followed by qualitative studies, likely a focused group model, taking an informative approach to selection, engaging initially GPs who self-identify as working at the ‘Deep End’ of deprivation.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE
Title: How changes in nutrient availability are sensed and shape metabolism and growth
Funder: Biotechnology and Biological Sciences Research Council

Abstract: In mammals nutrient signalling is a multi-layered network that embraces physiological, cellular (eg autophagy, see objective 4) and organ systems (eg neural). The network maintains the internal environment in the face of changes in the availability of nutrients, simultaneously adjusts metabolism to mitigate against those changes and tailors cell growth throughout the body to fit the nutritional circumstances. We remain ignorant of many molecular details and systems-levels principles by which this system works. There is increasing interest in the possibility of slowing or reversing the effects ageing by dietary manipulation and/or use of pharmaceuticals such as rapamycin (an mTOR inhibitor), PI3K inhibitors or metformin (an indirect activator of AMPK) that act to suppress nutrient signalling. To proceed down this road rationally it is important we understand the molecular basis of any strategy to minimise unwanted side effects. At the centre of nutrient signalling is mTOR, a protein kinase and integrator of signals relaying information about a cells current environmental conditions, including nutrients (most conserved and powerful are amino acids but also; cellular energy status as read-out by AMPK and nutrientsensitive growth factors such as insulin, IGF-1 and EGF), stresses and the cell cycle29. If cellular conditions are satisfactory mTOR is active and coordinates, via direct phosphorylation of targets and indirectly via many changes in gene transcription, increased lipid, nucleotide, protein and carbohydrate synthesis and ATP and NADH production (collectively termed anabolic metabolism) to support growth. If conditions are unfavourable mTOR is inactivated and engages a huge range of processes to adapt, including increased autophagy and reduced anabolic metabolic activity (collectively termed catabolic metabolism). Work with many model organisms supports the concept that the anabolic mode reduces, and the catabolic mode extends, life span.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: How autophagy and related processes are coordinated and important in adaption to changed nutrient availability and cell damage
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The increase in life span of model organisms subjected to DR is dependent on autophagy83 but the exact molecular mechanisms linking autophagy to ageing remain elusive. A major complication is that autophagy is part of one of the hallmarks of ageing namely loss of proteostasis while also contributing to several others such as deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence and stem cell exhaustion. Of note, up-regulation of autophagy by transgenic expression of ATG5 in mice extends health and life span2. The core process of autophagy is the generation of a double membrane bounded organelle that can engulf cell constituents and traffic them into the lysosomal compartment for recycling. Two protein machines control the initiation of autophagy, the ULK and Vps34 (class III PI3K) complexes. Together they remodel the ER to generate early autophagosomes that expand in an LC3- lipidation-dependent fashion. Autophagy operates in different contexts. If nutrients are scarce non-selective autophagy is induced by activation of AMPK and inactivation of mTORC1 and engulfs cytoplasm and/or organelles in autophagosomes of diverse size. There are forms of autophagy that proceed in the presence of ample nutrients (â€œselectiveâ€ autophagy, eg, mitophagy (autophagy of mitochondria), are targeted by cargo-selective autophagic receptors and appear to be insensitive to changes in mTORC1 or AMPK activity. Both nutrient-supply-sensitive and â€œselectiveâ€ autophagy are probably important for dietary-restriction-induced life span extension. Recent work has shown that molecular components of the autophagy pathway, including the machinery that lipidates LC3, have roles in other cell processes that can internalise and deliver extracellular material to lysosomes, eg phagocytosis, entosis and macropinocytosis. The molecular mechanisms that coordinate this non-canonical use of the autophagy apparatus, their roles in cell biology and how they dovetail with conventional autophagy are unknown.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Signalling mechanisms that determine the rate of ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Ageing can be driven by the accumulation of senescent cells in a tissue causing the emergence of a SASP phenotype (Senescence-Associated Secretory Phenotype) in which senescent cells drive more senescence and loss of tissue function. Ageing can also be driven by loss of cells, including those lost by specific programmed cell death mechanisms. Age related loss of axons and synapses is a major contributor to frailty in old age. Not only does it reduce neuromuscular strength but it impairs vision, memory, cognition and many other functions. Each requires functional innervation and malfunctions when axons are lost. Our work has delineated an ancient axonal survival pathway that appears to detect damage by sensing intracellular NMN levels. If NMN levels rise, something that is normally prevented by NMNAT2-mediated conversion to NAD+, a signalling pathway involving SARM1 is engaged that culminates in axon death. We have provided evidence this pathway, in which NMNAT2 acts as a survival-factor and SARM1 as death-inducer, contributes to neurone loss seen in ageing. We have data indicating neutrophils can sense nerve damage and the emergence of SASP, suggesting their accumulation could be an early biomarker and may shape the progression of these age-related problems. Recent work has indicated there is a DNA-methylation â€œclockâ€ that marks human age. The Epigenetics ISP has evidence the apparent age of this â€œclockâ€ in cultured cells can be reset by brief treatment with rapamycin via an unknown mechanism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: To study and manipulate heterogeneous epigenetic states that operate during ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: A central debate in ageing research is whether ageing is simply due to wear and tear, or to a hard coded ageing programme in our genes. While a decline in cellular and organismal functions with age might suggest the former, the large variability observed in the lifespans of closely related species may support the hypothesis that ageing is a regulated process. A number of biomarkers of ageing have been identified, such as telomere erosion and p16 expression. In mammals, ageing is accompanied by global changes in DNA methylation, characterised by global hypomethylation and focal hypermethylation (mainly of CpG islands). Recently, a â€œclockâ€ was described that can predict human chronological age based on specific changes at a discrete set of CpG sites throughout the genome65. This (DNAm) clock has since been shown not only to predict chronological age Â±3.6 years but also biological age, providing a potential measure of an organismâ€™s health in the context of its chronological age. For example, the clock of the liver â€œticksâ€ faster in individuals with fatty liver disease. Some organs however such as the cerebellum and potentially the placenta show a different methylation age trajectory.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of Metabolic Homeostasis
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The overall aim of Theme 4 is to provide a mechanistic understanding for the manner by which non-nutrient food and microbiota-derived food metabolites regulate the metabolism of lipids and carbohydrates and modulate overall energy expenditure to maintain and improve health. We will do that by focusing on the two major metabolic organs: the liver, where the transient influx of high concentrations of these metabolites will be exerting â€˜first-passâ€™ effects on lipid and glucose metabolism following their absorption from the gastrointestinal tract, and the organ-associated and peripheral adipocytes, where bioactive compounds can impact on energy sensing and expenditure. _x000D__x000D_ We will use human cell lines but also appropriate animal models to elucidate the role of nrf2 and sirt1 as the mediators of energy metabolism by food and their metabolites. In particular, we will use novel genome editing techniques by CRISPR/Cas9 in human hepatocytes, as well as sirt1 knockdown and overexpressed mouse models, developed in QIB. _x000D__x000D_ In addition, we will undertake human intervention studies with stably labelled fatty acids to enable quantification of hepatic and whole body fatty acid oxidation and lipid synthesis, in response to different diets developed in Theme 1. By combining the results obtained at the cellular and organ levels, we will gain a clear understanding of how diets regulate systemic metabolic homeostasis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: To study epigenetic mechanisms that create heterogeneity and functional diversity in stem cells, development and between individuals
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Single-cell technologies have revealed extensive heterogeneity between and within tissues, enabling important new questions in development and ageing to be experimentally addressed. During the course of the last ISPG, for example, we developed scBS-seq23 and the first combined method to sequence the transcriptome and epigenome (methylome) from the same single cell (scM&T-seq24). These new approaches have identified an exciting mechanism by which the creation of epigenetic heterogeneity can be connected with the generation of transcriptional heterogeneity. Building on this work, the new ISPG objective will investigate and model how epigenetic heterogeneity is established and, in turn, leads to diversification of cell phenotype and function during development and ageing. We will test the prediction that as cells transition towards a pluripotent state that is primed for lineage commitment, they acquire epigenetic marks including H3K27me3 and DNA methylation at regulatory regions that act to constrain the expression of developmental TFs25. Rapid turnover of these marks is expected to generate epigenetic heterogeneity between cells and thereby create transcriptional heterogeneity. We propose that this mechanism enables primed pluripotent cells to remain uncommitted, yet able to explore transiently different states that predispose cells toward different lineage choices upon receipt of differentiation stimuli. This informs an important new concept for understanding and controlling lineage commitment during stem cell differentiation and embryo development. In complementary work, using the model organism C. elegans, we have established that there is widespread heterogeneity in a subset of genes that are rate-limiting for ageing. We will, therefore, investigate how epigenetic and transcriptional heterogeneity is established between genetically identical organisms, and how such heterogeneity contributes to variability in key traits during ageing such as lifespan. This Objective uses mouse and human stem cells and C. elegans to explore the emergence and consequences of epigenetic heterogeneity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Transgenerational epigenetic inheritance: mechanisms and consequences for metabolism and ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Epigenetic changes that occur during the lifetime of an individual are generally not inherited by the next generation, as this could subvert epigenetic reprogramming events needed to reinstate totipotency. Yet, some genomic elements remain incompletely reprogrammed, and may thus represent a key genomic vehicle for transgenerational epigenetic inheritance47. Transgenerational inheritance requires that the germline remembers exposure to environmental changes and allows for these to be inherited to the next generation(s). Nutritional stress can mediate transgenerational memory through histone marks and small RNA pathways in invertebrates and DNA methylation changes in mice48,49. As observed in many studies, the inheritance mediated by epigenetic modifications reverts back to wild-type after one or a few generations. However, some epigenetic changes can lead to more permanent genome rearrangements, when coupled to genomic instability. For example, nutritional stress can lead to instability of high copy number ribosomal DNA (rDNA), resulting in copy number variation (CNV) at rDNA loci. There are many key aspects that remain unresolved in the field and this Objective tackles two essential questions: firstly, what are the mechanisms by which epigenetic reprogramming normally returns cells to a naÃ¯ve and totipotent stage and could these mechanisms thereby mediate transgenerational inheritance upon experimental manipulation. Secondly, can, and if so how could, stressors such as age and nutrition contribute to inheritance by modifying CNV through gametes with consequences for metabolism and ageing in subsequent generations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: To develop cutting-edge epigenomics and computational technologies
Funder: Biotechnology and Biological Sciences Research Council

Abstract: With the development of methods for genome-wide mapping of DNA methylation, histone modifications, chromatin accessibility and conformation, high-throughput sequencing has revolutionised the study and our understanding of epigenetics. In this ISPG, we have been at the forefront of methods development, including techniques for identification of new DNA modifications71,72, and low-cell and single-cell epigenomic methods, such as scBS-seq and scM&T-seq23,24. Integral to our IPSG objectives is the adoption and development of state-of-the-art techniques to enable us to interrogate epigenomic dynamics during the lifecourse â€“ to reveal the epigenomes of rare cells (as in early embryos), to uncover cell-to-cell heterogeneity in epigenetic states during key lineage decision making events, and to measure the extent of heterogeneity as a function of ageing â€“ and to integrate multiple parameters towards modelling epigenetic states and transitions. This objective is very much embedded within overall technology development at BI, and through our Sanger Institute/EBI Single Cell Genomics Centre links. This establishes a collaborative Cambridge environment that is hugely conducive to the development of novel epigenomics and computational methods. In addition, we shall extend interactions with industrial collaborators, such as Cambridge Epigenetix Ltd., in particular for developing targeted sequencing, and to commercialise IP we expect to develop in this area.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Using AI-Enhanced Social Robots to Improve Children's Healthcare Experiences
Funder: Economic and Social Research Council

Abstract: The main objectives of this research are as follows: (1) collaborating with stakeholders including children, parents, care-givers, and clinicians using a co-design strategy to specify the behaviour of a robot system designed to reduce children's pain and distress in a clinical setting; (2) implementing the developed strategy on an autonomous, responsive, flexible social robot, using state-of-the-art AI technology for social signal processing and robust decision making; (3) evaluating the impact of the robot through usability studies, as well as a formal clinical trial in the target clinical environment; and (4) critically assessing the role of social robots in the children's healthcare setting, ensuring that the introduction of robots into the clinical setting is done in an ethical and responsible manner that is beneficial to all.

Lay abstract: Children experience pain and distress in clinical settings every day, and the negative consequences of unaddressed pain can be both short-term (e.g. fear, distress, inability to perform procedures) and long-term (e.g. needle phobia, anxiety). In a series of small, innovative studies by project team members, a Nao humanoid robot has been used to deliver cognitive-behavioural therapy-based interventions during needle-based procedures. The results of these early studies have been positive, showing high acceptance among the target population as well as promising initial clinical results. However, these studies were all hindered by a critical technical limitation: in all cases, the robot was remotely operated and employed purely scripted behaviour with limited AI support, diminishing the flexibility and robustness of its behaviour as well as its potential to offer personalised, adaptive procedural support to children. In this project, we aim to address this limitation by developing and evaluating a clinically relevant and responsive AI-enhanced social robot. We believe that interaction with a robust, adaptive, socially intelligent robot can effectively distract children during painful clinical procedures, thereby reducing pain and distress.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: SG Health Inequalities ESRC Fellowship
Funder: Economic and Social Research Council

Abstract: Each fellowship will last up to 18 months to cover a three-month inception phase for set up activity, followed by a 6-12-month placement with the host organisation, and concluding with an impact phase lasting up to three months. Fellows will co-design projects and activities with their host and produce analysis to inform government decision-making across a range of policy priorities. Fellows will also engage across the host organisation, building effective working relationships and supporting wider knowledge exchange with researchers. This will be supported through their embedded role within the host organisation, including line management support.

Lay abstract: Each fellowship will last up to 18 months to cover a three-month inception phase for set up activity, followed by a 6-12-month placement with the host organisation, and concluding with an impact phase lasting up to three months. Fellows will co-design projects and activities with their host and produce analysis to inform government decision-making across a range of policy priorities. Fellows will also engage across the host organisation, building effective working relationships and supporting wider knowledge exchange with researchers. This will be supported through their embedded role within the host organisation, including line management support.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: GENERIC HEALTH RELEVANCE