NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Do psychedelic drugs have long-term implications for structural and behavioural plasticity in a mouse model?
Funder: Wellcome Trust

Abstract: Plasticity describes changes at various levels of organisation of the nervous system which result from experience. It is hypothesized that psychedelic drugs can induce plasticity at cellular, structural and functional levels, aiding lasting remission from numerous neuropsychiatric disorders. They offer a unique opportunity to study heightened plasticity as a potential neural pre-requisite of behavioural flexibility. Using a mouse model, I aim to determine whether psychedelics induce long-term anatomical and behavioural plasticity changes and to determine if the context of drug administration affects the quality of on- and off-drug experience. Our approach will be a combination of (1) behavioural investigations of the quality of on-drug psychedelic experience under different contexts and of off-drug effects on cognitive flexibility, (2) longitudinal off-drug structural MRI imaging, and (3) in-vivo microelectrode array electrophysiology to understand single network function and information processing. These studies will elucidate whether the psychedelic-induced structural and functional changes persist after the acute intoxication phase and if they can help explain the lasting behavioural changes that have been observed in human studies.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Does maternal immunity to SARS-CoV-2 protect against SARS-CoV-2 infection in infants under 12 months old in Scotland?
Funder: Medical Research Council

Abstract: We will test the hypothesis that maternal SARS-CoV-2 immunity is associated with protection against SARS-CoV-2 infection in infants under 12 months old. We will undertake two case-control studies. Study 1 will compare infants born in Scotland 1/8/21-31/7/22 with PCR-confirmed SARS-Cov-2 infection in the first year of life to infants without SARS-CoV-2 infection in the first year of life, matched 1:4 by date of birth, to determine: a) the odds of maternal COVID-19 vaccination prior to delivery b) the odds of maternal vaccination prior to pregnancy versus vaccination during pregnancy versus no vaccination  c) the odds of maternal SARS-CoV-2 infection prior to delivery d) the odds of maternal SARS-CoV-2 infection prior to pregnancy, versus SARS-CoV-2 infection during pregnancy, versus no infection e) the odds of maternal SARS-CoV-2 infection during the first year after delivery. Study 2 will compare similar cases/controls, but limited to Greater Glasgow & Clyde and matched 1:2 by date of birth, to determine: a) the odds of maternal SARS-CoV-2 IgG seropositivity during pregnancy b) the odds of detectable SARS-CoV-2 neutralising antibodies during pregnancy c) the odds associated with maternal SARS-CoV-2 IgG concentration. Case/controls and linked maternal data will be identified from routinely collected NHS and national records data. Data on confounding factors will include infant sex, gestation, maternal age, ethnicity, and deprivation index. In study 2, excess blood from antenatal screening will be used to undertake SARS-CoV-2 IgG MSD-ECL assay and neutralisation assays. Using conditional logistic regression, a multivariable model will be created to explore the interactions between maternal SARS-CoV-2 infection/immunity/COVID-19 vaccination, and other demographic/socio-economic predictors of infant SARS-CoV-2 infection. Data will be linked and pseudo-anonymised within NHS Safe Haven. Use of unconsented data will be approved by ethics/privacy committees.


Research Activity Codes: 3.4 VACCINES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Does place matter? An examination of geographical inequalities in COVID-19 in England
Funder: The Health Foundation

Abstract: Early in the COVID-19 pandemic, the perception was that ‘we are all in this together’ and that the virus ‘does not discriminate’. However, government data has since highlighted that deaths from COVID-19 are almost double in poorer communities and higher in places with larger black, Asian and minority ethnic populations.

This has led to concerns that not everyone is experiencing COVID-19 in the same way. But we do not know enough about why or how this might change over time.

In this project, a team from Newcastle University will use several sources of data to understand how the COVID-19 pandemic has developed over time in different types of places and communities.

The project team will use information on virus cases and deaths in each area to understand how these are impacted by living and working conditions, housing, employment and access to services and leisure facilities, for example.

This work will help to uncover how and why some communities are affected more than others by COVID-19, and to identify which ones are more at risk from future waves and other pandemics. This will also help staff in public health, social care and the NHS provide better support to high-risk communities.

The results of this work will be published on a website that will use maps to show differences in the pandemic across the country. The results of the research will help with local NHS and public health planning, as well as in policy development, media and parliamentary debates.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Does the central noradrenergic system play a role in agitation in Alzheimer's disease?
Funder: Medical Research Council

Abstract: BACKGROUND: The locus coeruleus (LC), the major source of the brain's noradrenaline (NA), undergoes early neurodegeneration in Alzheimer's disease (AD). The LC upregulates arousal in response to stress via connections with the amygdala and prefrontal cortex to perform emotion regulation and response inhibition. Agitation in dementia (defined as emotional distress associated with motor overactivity, verbal or physical aggression) is distressing, common and difficult to treat. My systematic review on the neurochemistry of agitation in AD found the strongest evidence for compensatory postsynaptic overactivity secondary to LC neuron loss. LC signal intensity, a valid indicator of LC integrity, can be measured using magnetic resonance imaging (MRI) in vivo. KEY GOALS: To investigate whether the central NA system plays a role in agitation in AD, the study will ask: 1) Is lower structural LC integrity in early AD associated with agitation? 2) Is agitation associated with deficits in emotion dysregulation (increased sensitivity and reactivity to threat) and poor response inhibition, and does this explain any association between LC integrity and agitation? 3) Does propranolol (a centrally active beta-blocker) modulate emotion dysregulation and response inhibition in patients with AD and healthy older adults? METHODOLOGY: The study will recruit 50 patients with mild-moderate AD and 50 healthy older controls. The AD group will undergo MRI to assess LC structural integrity and LC-amygdala coupling during perceived threat. The AD and control group will complete behavioural tests and receive a single 40mg dose of propranolol to assess the effect of NA blockade on cognition (sensitivity to perceived threat, inhibitory emotional control and motor response inhibition).  OPPORTUNITIES: This study could inform new biomarkers to identify/stratify individuals with AD prone to agitation and lead to new therapies (e.g. beta-blockers) for study in future clinical trials.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Double Trouble: The effect of violent conflict on the abuse and misuse of prescription and non-prescription medicine in the MENA region
Funder: The British Academy

Abstract: Violent conflict has a profound and detrimental effect on public health when civilians are injured, diseases spread and health infrastructures collapse. This project builds upon previous collaboration between the applicants to investigate an often neglected aspect of public health during conflicts: the impact of violent conflict on the abuse and misuse of prescription and non-prescription medicines ('drugs') amongst local populations. It combines Conflict Studies and Medical Sociology to understand the impact of different forms of violent conflict on patterns and levels of drug abuse/misuse in four MENA region countries: Iraq, Libya, the Syrian Arab Republic and Yemen. The study uses a quantitative survey and semi-structured interviews with community pharmacists to gather data about pharmacists' experiences, perceptions and responses to drug abuse/misuse in conflict societies. The results and recommendations for more effective identification and management will be disseminated to non-academic user audiences in the public health infrastructure of the countries involved.


Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS
Health Categories: MENTAL HEALTH;DISPUTED AETIOLOGY AND OTHER
Award Title: Dynamic Imaging in Viral Encephalitis Defines Unique Roles for Chemoattractants.
Funder: Medical Research Council

Abstract: BACKGROUND Herpes simplex virus (HSV) encephalitis is a devastating disease of brain inflammation characterised by blood-brain barrier (BBB) breakdown and leucocyte migration, particularly early neutrophils, forming perivascular 'cuffs'. No immune therapy is established therefore 10-30% die and most survivors have neurological morbidity. Targeted therapy which mitigates deleterious leucocyte migration and BBB breakdown is desperately required. Leucocytes migration is determined by chemokines, but increasingly atypical chemoattractant proteins/receptors are recognised. However, their role in neutrophil migration and behaviour in the brain, such as the production of neutrophil-extracellular traps (NETs), are not known.  Together the Co-PIs have the individual techniques to image this in real time by Multiphoton Intravital Microscopy (MP-IVM). AIM Determine the relative contribution of typical/atypical chemoattractants on neutrophil migration into the brain and the behaviour driving BBB breakdown. SPECIFIC AIMS 1. Establish specific neutrophil migration behaviours which are associated with BBB breakdown in a murine model of HSV encephalitis. 2. Determine the contribution of typical/atypical chemoattractant receptor/ligand interactions driving this behaviour. 3. Interrogate the differential production of NETs and associated processes in BBB breakdown METHODS 1. In an intrathecal murine model of HSV inoculation, neutrophil migration and BBB breakdown will be imaged by MP-IVM in LysM-Green Fluorescent mice. Typical/atypical chemoattractant expression will be determined by RT-Polymerase Chain Reaction and confirmed by Enzyme-Linked Immunosorbant Assay. 2. Candidate chemoattractants in knock-out or antibody-treated mice will be interrogated by MP-IVM in relation to neutrophil migration and BBB breakdown 3. NETs will be imaged by MP-IVM and single-cell RNAseq of transmigrated neutrophils will explore associated processes in the UK Co-PI's BBB model


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Dynamic Structural Biology: New Tools and Strategies for General Applications
Funder: Wellcome Trust

Abstract: X-ray crystallography and cryo-EM are essential tools for structural biologists, but these data are almost always from samples held at 100 K. Life is dynamic and function is not compatible with the cryogenic conditions. X-ray Free Electron Lasers (XFELs) offer new opportunities because their unparalleled intensity reduces the crystal size requirements such that even submicron size crystals yield high quality structures.1-3 The fs pulse provides extraordinary temporal resolution and data without radiation-induced alterations.4-9 XFELs are motivating new serial data collection methods at room temperature.10-13 Synchrotron beamlines like Diamond’s VMXi with high-flux, micro-focus, and fast detector are also pushing serial methods that complement XFELs.
 
 
 
What is critically missing are tools to manipulate microcrystal samples and to correlate enzyme kinetics, spectroscopy, and time-resolved structural biology. Therefore, the specific aims of this proposal are to i) extend and generalize experimental methods in enzyme kinetics to microcrystalline samples, and ii) and iii) to develop time-resolved structural biology in general at XFELs (ii) and at synchrotrons (iii). In particular, we will correlate room-temperature, serial crystallographic and spectroscopic data to determine the electronic and atomic structures of metalloenzymes engaged in catalysis. Some of our enzymes create Fe(IV)=O intermediates, whereas beta-lactamases are responsible for antimicrobial resistance.

Lay Abstract: To capture atomic resolution "movies" of macromolecules engaged in function has been a grand challenge in structural biology since Nobel laureate Max Perutz attempted to measure the structural impact of O2 binding to hemoglobin crystals. His large crystals cracked when he tested this function because it triggered significant conformational dynamics. We are currently experiencing a step-change in time-resolved functional studies linked to serial femtosecond crystallography. This room temperature technique exploits micron-size crystals and fs pulses from X-ray Free Electron Lasers (XFELs, new sources that are 9-orders of magnitude brighter than synchrotrons like Diamond Light Source). We will will correlate room-temperature, serial crystallographic and spectroscopic data to determine the time-resolved electronic and atomic structures of metalloenzymes engaged in catalysis. Both types of data come from the same sample and X-ray pulse. Some of our target enzymes use O2 to create reactive Fe(IV)=O intermediates, whereas beta-lactamases are responsible for antimicrobial resistance.

Research Activity Codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;1.4 METHODOLOGIES AND MEASUREMENTS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Dynamic integration of ingestive behaviours and homeostasis by hypothalamo-neurohypophysial system glucagon like peptide 1 receptors
Funder: Medical Research Council

Abstract: This proposal aims to characterise the exact physiological roles of gut peptide receptor GLP-1R in the hypothalamo-neurohypophysial system (HNS) of female and male rats. We will use adeno-associated viruses (AAVs) delivered by stereotaxic surgery to the rat brain. The AAV retrograde capsid variant, AAV2-retro, enables retrograde access to projection neurones including nucleus tractus solitarius (NTS) to supraoptic nucleus (SON) projections. We will firstly determine the neuropeptide identities of retrograde labelled NTS neurones projecting to the SON by RNAscope. We will inject AAV2-retro-Cre into the SON which will retrogradely trace back to mark NTS connecting neurones. We will deliver a separate Cre-dependent AAV directly to the NTS in the same surgery, for example, AAV FLEx system shRNA targeting the preproglucagon mRNA. In all studies we will investigate, feeding and drinking, hormone release, and cell signalling pathways. We will knockdown SON Glprs using AAV-shRNAs and investigate postprandial responses in a fasting-refed rats as well as schedule-fed rats to identify effects on feeding circuits. We will use state-of-the-art biosensor cells to precisely monitor the real-time release of vasopressin and oxytocin in SON and posterior pituitary explant cultures maintained in a dish. We will investigate the short-term and longer-term consequences of daily liraglutide treatment on the rat SON and pituitary gland by exploring proteome-wide phosphorylation changes by phosphoproteomics. We further plan to recruit healthy human volunteers (male and female) as part of a randomized crossover trial to determine the short-term actions of liraglutide on HNS hormone release. This project will inform about how the HNS integrates responses from food and fluid intake to maintain homeostasis. These data may help with design and development of new drugs for more targeted methods of activating receptors at specific sites, and thus influence therapeutic strategies.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Dynamic regulation of human immunity by Interferon Regulatory Factor 8 (IRF8)
Funder: Medical Research Council

Abstract: Human immunity critically depends upon the coordinated production of functionally specialised cells by haematopoiesis, under the control of lineage-specific transcription factors (TFs). Rapid adaptation of haematopoiesis is required to meet the demands of immunity, especially in the production of innate myeloid cells; neutrophils, monocytes and dendritic cells (DCs). Interferon regulatory factor 8 (IRF8) is a pioneer TF for myeloid cells and critical lineage-determining TF for DCs. IRF8 plays a pivotal role in demand adaptation as illustrated by predominant granulopoiesis and monocyte/DC depletion in IRF8 deficiency, the association of IRF8 variants with blood parameters and immune diseases, and suppression of IRF8 in sepsis and cancer.  In Aim 1 I will use single cell multiomic genetic and epigenetic approaches to achieve an integrated analysis of the chromatin architecture of the IRF8 locus, genome-wide chromatin occupancy by IRF8 and associated regulatory networks, mapped in developmental time and across myeloid cell lineages. Extending these approaches to Aim 2, I will determine the changes in IRF8 expression, chromatin occupancy and enhancer activation driving abnormal haematopoiesis in patients with sepsis and breast cancer. This will identify regulatory networks and mechanisms that are modified by disease. In Aim 3, I will define the effects of rare, loss-of-function mutations in IRF8 on downstream activities and analyse protein structure-function relationships as potential therapeutic targets. Finally in Aim 4, I will determine the effect of variations in regulatory regions on the lineage-specific and dynamic expression of IRF8 by eQTL analysis to fine-map the architecture of IRF8 regulation.  Together these approaches will define the dynamic role and regulatory mechanisms of IRF8 in immune cell haematopoiesis with the ultimate goal of targeting IRF8 to manipulate immune responses for therapeutic gain.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Early detection of oesophageal adenocarcinoma (OAC) from Barrett’s oesophagus (BO): defining genetic and microenvironmental drivers of BO-OAC transition
Funder: Cancer Research UK

Abstract: Background: Oesophageal adenocarcinoma (OAC) is a deadly disease whose incidence has increased substantially in recent years. OAC is preceded by a well-identifiable pre-cancer condition named Barrett’s oesophagus (BO). However, not all BOs will transform into OAC and the transition from BO to OAC remains hard to predict due the scarcity of effective tools for early detection. Currently, BO surveillance is achieved through endoscopic monitoring, which is a costly and invasive procedure that could be reduced with reliable molecular and cellular markers of BO-OAC transition for early patient stratification.

Aims: The purpose of this research is to study the transformational events triggering BO-OAC transition at the molecular and cellular level to enhance early detection. Our preliminary data show that patients with BO can be divided into groups based on their genetic and tumour microenvironment drivers. We propose that the early identification of these drivers can be used to inform OAC early diagnosis. Leveraging on the complementary expertise of our team, we propose to:

- Integrate the study of genomic and tumour microenvironment data to derive BO-OAC transition groups
- Correlate these groups with disease prognosis
- Characterise them experimentally
- Validate their use as markers of progression in a case-control cohort

Methods: We will compare genomic and transcriptomic alterations across hundreds of BO-OAC pairs and divide them into groups according to the drivers of transition from pre-cancer condition to fully transformed cancer. We will then use high-dimensional immune profiling to characterise the microenvironment of these BO-OAC groups and correlate their molecular and cellular features to prognosis. Finally, we will characterise the driver potential of the alterations across groups in co-cultures of patient-derived epithelial and stromal cells and validate their use as early detection markers in a case-control cohort.

How the results of this research will be used: This research will be useful to: 

- Identify the diverse molecular routes leading to OAC
- Associate them with the cellular environment that surrounds the tumour
- Inform discovery of molecular and cellular biomarkers predictive of BO transformation

The knowledge gained from this study will underpin better risk stratification biomarkers to be tested in future clinical trials.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS