NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Investigating antibody affinity maturation during B cell exhaustion in viral infection
Funder: Medical Research Council

Abstract: The humoural immune system continuously attempts to clear chronic infections where antigen persists. An example of this is HIV infection where anti-viral antibodies continue to be produced until the immune system eventually collapses. Longitudinal sampling shows that the virus mutates to become resistant to antibody neutralisation over time. However, antibodies then develop to neutralise the mutated virus pressuring the virus to mutate again. Recent studies of the co-evolution of antibodies and virus highlight the great selection pressure the antibodies exert on the virus. Thus, it would be advantageous for the virus to employ additional mechanisms to evade humoural responses. I hypothesise that one mechanism is to drive antigen-specific B cells to an exhausted phenotype. This undermines the effectiveness of the immune response by side-tracking HIV-specific B cells away from differentiation into antibody secreting long-lived plasma cells. Chronic infections, including HIV, result in increased frequencies of exhausted B cells (CD21low/CD27low cells). In this study, HIV-specific B cells will be separated by FACS using autologous envelope protein probes. Exhaustion markers will be quantified allowing correlation of antibody affinity for HIV with B cell exhaustion at a single cell level. In addition, transcriptional profiling of each B cell will allow greater definition of their exhaustion phenotype. This will allow evaluation of whether the exhausted subset acts as an alternative cell fate for the B cells that are most highly affinity-matured. To establish whether B cell exhaustion aids virus escape from neutralising antibodies, I will use flow cytometric analysis of longitudinal samples to link the frequency of exhausted B cells with the ability of virus to escape contemporaneous serum neutralisation. From this work I will define whether virus-induced B cell exhaustion limits the appearance of neutralising anti-HIV antibodies and thus contributes to immune evasion.


Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Investigating compounds to increase the efficacy of antimicrobials used for targeting Helicobacter pylori
Funder: Wellcome Trust

Abstract: The bacteria Helicobacter pylori (H. pylori) is a pathogen that infects the stomach of ~50% of the population, and can led to the development of peptic ulcers and gastric cancer. Although the treatment currently consists of a triple therapy of antibiotics and proton pump inhibitors, many strains have developed a resistance to antibiotics, and the disease can recur within a patient. H. pylori also colonises the stomach within a thick mucus layer, which can prevent drugs from reaching the site of infection. Two compounds have been found to increase the effectiveness of antibiotic therapy against resistant strains within patients; bismuth salts and the long term use of aspirin. I will conduct further research on ways to use these therapies in combination with antibiotics in order to provide a more effective treatment. I will also explore the possibility of encapsulating bismuth salts in a protective protein shell (apoferritin) to aid drug delivery across the stomach mucous. Using additional treatments alongside the antibiotics in treating H. pylori infection may increase their efficacy, and prevent the disease recurring. Elimination of the disease in a patient would also reduce the need for repeated antibiotic treatment, which can lead to incidences of antimicrobial resistance.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INFECTION
Award Title: Investigating genetic and environmental risk for psychosis mediated through L-Type voltage gated calcium channels
Funder: Medical Research Council

Abstract: Both genetic and environmental factors are known to be important in determining risk for the major psychotic disorders such as schizophrenia and bipolar disorder. Genomic studies have identified genetic variants in L-Type Voltage Gated Calcium Channels (L-Type VGCCs), particularly in the CACNA1C gene, as strongly associated with risk for both schizophrenia and bipolar disorder. Exome sequencing studies of schizophrenia have further confirmed an excess of mutations in L-Type VGCCs in patients compared to controls. This highlights the importance of understanding the molecular and behavioural consequences of mutations in L-Type VGCCs in relation to psychiatric disorders. Calcium entry through L-Type VGCCs plays a critical role in controlling neuronal gene expression and neuronal plasticity. To characterise the specific effects of mutations in CACNA1C associated with psychosis we will investigate the effects of reduced CACNA1C gene dosage on behaviour and the control of gene expression. We will use a novel hemizygotic deletion rat model (Cacna1c +/-) that recapitulates the predicted effects of deleterious point mutations in CACNA1C associated with increased risk for schizophrenia. We will investigate the effects of reduced dosage of Cacna1c on behaviour, focussing on changes in associative learning, and on molecular pathways involved in the regulation of plasticity. We will also investigate the effects of early life stress on the molecular pathways regulated by Cacna1c, building on our recent finding that pre-pubertal stress results in sustained reductions in Cacna1c expression. Finally we will determine whether juvenile stress exacerbates psychosis-related behavioural phenotypes and changes in gene expression in Cacna1c hemizygous deletion animals. This work will be an important step in advancing understanding of the mechanisms through which a major genetic risk locus for psychosis impacts on brain function and how genetic risk interacts with environmental risk.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH
Award Title: Investigating lung regeneration and repair pathways in Cystic Fibrosis
Funder: Medical Research Council

Abstract: Cystic Fibrosis (CF) is a lethal genetic condition affecting over 10,000 people in the UK. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator(CFTR) gene leading to decreased function of the CFTR chloride channel. CF patients develop a destructive lung disease as a consequence of this, associated with significant morbidity and mortality. Despite advances in care, the median age of death is 32, and the only cure for advanced lung disease is transplantation. Novel CFTR modulators partially correct the abnormal chloride transport in CF and have significant effects on mucus clearance and lung function, but leave patients with residual lung damage.  Basal cells are present throughout the human airways and migrate and proliferate in response to injury, acting as stem cells. They produce different progeny cells in steady state and repair, so may be an excellent target to develop strategies that augment lung repair.   Aims: 1. To phenotype basal cells from people with CF compared to healthy controls in terms of gene expression, proliferation and migration. 2. To assess proliferation and differentiation of CF 3D organoid culture compared to healthy controls and assess regenerative capacity after injury 3. To test whether CFTR modulators affect basal cells and can promote repair in 3D organoid culture. 4. To compare clinical outcomes following CFTR modulator therapy in people with CF with novel outcomes of repair and established measurements of inflammation. Methods: I will undertake basal cell culture and 3D organoid culture of patients with CF and healthy controls. These will then be characterised with RNAseq, qPCR, and immunohistochemistry. Migration and proliferation assays will be performed. Basal cells and organoids will be co-cultured with CFTR modulators to compare with clinical outcomes in vivo. The potential of lung tissue to regenerate and repair is accepted but has not been extensively studied, particularly in CF.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health Categories: CONGENITAL DISORDERS
Award Title: Investigating protein synthesis during dormancy in Pseudomonas aeruginosa
Funder: Wellcome Trust

Abstract: Much of our understanding of bacteria, and the biological processes which sustain them, comes from the study of rapidly growing populations in nutrient-rich conditions. However, in natural environments and during infections, bacteria are often stressed and starved of key nutrients. Upon starvation, many bacteria dramatically reduce biological processes and effectively enter a hibernating state where they become highly tolerant of antibiotics. I’m interested in how bacteria regulate this state of dormancy, both at the single-cell level and across populations of cells. Specifically, since data suggest that rates may fluctuate between cells, I’m interested in how protein synthesis is coordinated in time and space during starvation and how these dynamics relate to antibiotic susceptibility. Using the opportunistic pathogen Pseudomonas aeruginosa, I will label and analyse protein synthesised during starvation via fluorescence microscopy and FACS. By employing a FACS-based Tn-Seq screen and mass-spectrometry to find proteomic changes, I will identify, validate and characterise regulators of protein synthesis during starvation. This study will provide both a descriptive and a mechanistic understanding of protein synthesis during bacterial starvation, giving insights into how this activity coordinates with cellular physiology and contributes to antibiotic tolerance.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Investigating the behavioural and neurobiological effects of SSRI discontinuation in mice
Funder: Wellcome Trust

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression in the UK. However, they have long been known to cause adverse symptoms upon abrupt discontinuation, including heightened anxiety, sleep disturbances, nausea and dizziness. Despite evidence that over half of patients will experience SSRI discontinuation symptoms, there is very little research on the condition or its causes. This project aims to study the effects of discontinuation of long-term treatment with the SSRI paroxetine, in adult mice. First, we will optimise a protocol of long-term paroxetine treatment and discontinuation. Behavioural measurements of key SSRI discontinuation symptoms, including anxiety, will then be measured during the discontinuation period. Discontinuation symptoms may be caused by the rapid depletion of the neurotransmitter 5-hydroxytryptamine (5-HT), hence a combination of modern neuroscience techniques including large-scale monitoring of 5-HT neuron firing and high-speed measurement of 5-HT release dynamics will be used to explore this possibility. Finally, we will use a chemogenetic approach to precisely manipulate 5-HT neurons to investigate their causal role in SSRI discontinuation symptoms. We hope this research will elucidate the underlying mechanisms of SSRI discontinuation symptoms and will place us in a good position to deliver clinical advances vitally needed in this area.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Investigating the biological function of the E3 ligase, HOIL-1
Funder: Wellcome Trust

Abstract: Ubiquitin is a small protein that is attached to different targets affecting their subsequent behaviour. This addition can ‘tag’ the target for destruction by the cell, affect its localisation or promote various interactions with other proteins. E3 ligases are a group of enzymes responsible for the addition of ubiquitin onto a target, and I am interested in an E3 ligase termed HOIL-1. People who lack HOIL-1 accumulate abnormal glucose deposits called polyglucosan in their cardiac tissue, leading to heart failure. These observations suggest that HOIL-1 has a critical role in preventing the accumulation of such deposits and the overall goal of my project is to discover how this is achieved. In my initial experiments, I found that HOIL-1 is able to attach ubiquitin to glucose and thus, I hypothesise that by tagging with ubiquitin, HOIL-1 marks this molecule for destruction. People lacking HOIL-1 cannot initiate destruction and therefore accumulate the abnormal polyglucosan deposits. My aim for this project is to gain insight into how ubiquitin is added by HOIL-1. Furthermore, I aim to identify additional targets associated with HOIL-1. By discovering its targets, we can further understand its role within the human body and consequently, its potential role in disease.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Investigating the clinical utility of the type-I interferon signature as a predictive biomarker for response to rituximab, and understanding how it drives B cell dysfunction in SLE
Funder: Versus Arthritis

Abstract: B cells are central to the pathogenesis of systemic lupus erythematosus (SLE), thus providing the rationale for the use of rituximab (B cell depletion) therapy. However, not all SLE-patients respond to rituximab, and upon  B cell repopulation some patients relapse.

In addition to B cell abnormalities, an upregulation of interferon (IFN)-I-induced genes in the blood (IFN-I signature) has been identified in 60-80% of SLE-patients. We have recently demonstrated that the concentration of IFNα is critical in determining the fate of immature-naive B cell maturation. At lower concentrations of IFNα, B cells differentiate into both plasmablasts and immunosuppressive regulatory B cells (Bregs), whereas at higher concentrations the B cell response is channelled towards plasma cell maturation. Furthermore, SLE-patients with an elevated IFN-I signature show a skewed response towards autoantibody-producing plasma cells and reduced Breg frequency.

We hypothesize that an elevated IFN-I signature in SLE-patients predetermines clinical response to rituximab-therapy. We propose that the lack of response is due to high levels of IFNα inhibiting the differentiation of newly repopulated immature B cells into Bregs whilst promoting autoantibody production. To test this, we propose to screen SLE-patients prior to and after rituximab for IFNα-signature, autoantibodies to IFNα, Breg frequency/function, and autoantibody-producing plasma cells. We will evaluate how signals downstream of the IFNα receptor on B cells change in response to increasing concentrations of IFNα, and whether inhibiting certain signals restores Breg function in SLE-patients. Furthermore, we will assess how IFNα alters chromatin accessibility and transcriptional output of the IL-10 locus on immature B cells in rituximab-treated SLE-patients that relapse after B cell repopulation.

Our work will provide a novel tool to predetermine response to rituximab. Identification of the biological pathways by which high-levels of IFNα inhibit Breg differentiation could lead to new therapies, and also benefit patients with other IFNα-driven autoimmune diseases.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Investigating the cytoprotective role of NRF proteins against drug-induced cardiovascular toxicity
Funder: Wellcome Trust

Abstract: Many drugs used to treat cancers and HIV cause life-threatening heart problems which limits their use. Research into how to reduce this risk has previously been difficult due to a lack of experimental methods which accurately mimic the human cardiac system. However, new 3D human-cell models have been developed which reproduce the adverse drug reactions seen in patients. These new models have been used to show that increased expression of an important protective protein NFE2L (NRF2), provides protection from the toxic effects caused by a commonly used breast cancer drug. We believe that by increasing the activity of human NFE2L proteins (NFE2L1-3), we may protect cardiac cells from other adverse drug effects. Here, we will combine 3D human cardiac models with gene editing methods and advanced cell imaging techniques to manipulate expression of all NRF family proteins and monitor the protective effects under normal and high-glucose conditions, which are known to reduce the protective effects of NRF2. The results from this study will aid the development of new therapeutic strategies to prevent or reverse heart toxicity from commonly used cancer and HIV drugs.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CARDIOVASCULAR
Award Title: Investigating the epidemiology of endemic Giardia in Scotland using a whole genome sequencing approach
Funder: Chief Scientist Office, Scotland

Abstract: The Scottish Parasite Diagnostic and Reference Laboratory and Health Protection Scotland have established that the majority of Scottish cases of the gastrointestinal parasite Giardia duodenalis are acquired locally rather than being travel-related; the source of infection in most cases is unknown. We will investigate molecular diversity and epidemiology of Giardia in Scotland using whole genome sequencing (WGS). We will develop a novel WGS-based parasite genotyping system, applying it to a large collection of human isolates collected in Scotland, to determine molecular types and to identify genetically-linked clusters of cases. Information will be integrated with metadata from Health Protection Scotland to improve understanding of Giardia epidemiology. We intend to improve healthcare in Scotland through (a) increasing capacity to characterise parasites at a molecular level, (b) determining the presence and distribution of zoonotic strains and (c) developing molecular/bioinformatic tools to underpin disease surveillance and control, allowing evidence led changes to laboratory testing policies. The tools developed in this project will permit the identification of genetically-linked clusters of cases, allowing for the detection and management of outbreaks. These tools can also be used to trace transmission routes in order to provide evidence for risk assessment.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Investigating the functional basis of shared genetic etiology across autoimmune diseases
Funder: Wellcome Trust

Abstract: Autoimmune diseases are a diverse set of conditions afflicting ~10% of the population worldwide, they pose a substantial personal and socioeconomic burden, and they have no cure. Currently prescribed treatments have variable efficacies and can be associated with severe side effects such as malignancies and even fatal opportunistic infections. Designing improved therapeutic strategies requires a better understanding of the pathways that drive these conditions to achieve an optimal modulation of the immune system.
 
 
 
Investigating the biological consequences of disease-associated genetic variants provides an avenue for delineating critical pathophysiological mechanisms. However, for each of these conditions, tens to >100 different loci have been found to influence disease risk. Therefore, prioritization is required, and the approach taken in this proposal is to focus on genetic variation shared across multiple autoimmune diseases, including a polymorphism in the tyrosine kinase 2 (TYK2) gene that protects against no fewer than 11 such conditions. The key goals of this research are to (i) investigate the molecular basis of shared genetic risk across autoimmune diseases; (ii) elucidate the downstream signatures and impact of shared genetic risk to help define key disease pathways; and (iii) investigate how key disease pathways can be fine-tuned for maximal benefit.

Lay Abstract: Autoimmune diseases are thought to arise when cells of the immune system - which normally fight off infections - become inappropriately activated and instead mount a response against the body leading to pervasive tissue damage. These diseases, which include conditions such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease, are estimated to afflict ~10% of the population worldwide. They pose a substantial personal and socioeconomic burden and they have no cure.
 
 
 
There is a fundamental need to develop improved therapeutic strategies to treat these diseases through an optimal modulation of the immune system - that allows substantial symptom alleviation - but without leading to the severe or even fatal side effects that can occur with currently available treatments. Interrogating the biological consequences of genetic factors that contribute to the development of multiple autoimmune conditions provides an approach for elucidating key mechanisms underpinning these diseases. The proposed research aims to (i) investigate the basis of shared genetic risk across different autoimmune conditions at the molecular level; (ii) elucidate the downstream cellular changes arising due to the genetically determined molecular differences to help define key disease pathways; and (iii) investigate how key disease pathways can be optimally regulated.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM