NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the metabolic, inflammatory and epigenetic pathways underlying increased risk of pregnancy complications in overweight women.
Funder: Wellcome Trust

Abstract: My research will analyse the relationships between obesity and a number of advadverse pregnancy outcomes through a detailed investigation of metabolic, inflammatory and epigenetic pathways. The research will draw on analytical agtechniques from genetic and epigenetic epidemiology in order to assess the causal associations between: profile (including during pregnancy) - Body mass index and pregnancy outcomes (including birth weight, gestational age, pre-eclampsia and maternal hypertension) uding during pregnancy) - Body mass index and metabolic profile (including during pregnancy) - Body mass index and inflammatory markers (including during pregnancy) - Metabolic profile and inflammatory markers (including during pregnancy) - Metabolic profile and pregnancy outcomes - Inflammatory markers and pregnancy outcomes - Obesity and epigenetic profile in mothers and offspring - Pregnancy outcomes and epigenetic profile in mothers and offspring - Metabolite levels and epigenetic changes, with respect to pregnancy outcomesA key goal would be to obtain a first-author publication for several of the stated objectives. Ultimately, it is hoped that any causal associations found between body mass index, pregnancy outcomes and the intermediate phenotypes listed will improve knowledge of the pathological mechanisms involved in the relationship between maternal obesity and adverse perinatal outcomes. Further public health efforts could then be made to reduce levels of maternal obesity or levels of intermediate metabolic or inflammatory biomarkers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Investigation of immune and haematopoietic disorders
Funder: Medical Research Council

Abstract: Allergic asthma is characterised by uncontrollable airways hyperresponsiveness (AHR) induced by a variety of provocative stimuli and is associated with type-2 inflammatory infiltrates into the lungs. The number of sufferers has increased dramatically over recent decades and the World Health Organisation estimates that in the region of 300 million people worldwide suffer from this disorder. Genes residing on human chromosome 5q31-34 have been implicated in the induction and progression of several immune and haematopoietic disorders including asthma and allergy, autoimmunity, parasite susceptibility, and myelodysplasia. We combine information derived from the human and mouse genomes, with techniques to modify the mouse genome to identify and define the functions of disease susceptibility genes. Using transgenic mouse models we have characterised fundamental inter-dependent roles for the type-2 cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13 as mediators of asthma and allergy. More recently we have focussed on characterising critical molecules that initiate the type-2 response. These include IL-25 and IL-33. IL-25 is a member of the IL-17 family of cytokines and we have demonstrated an important role for IL-25 in protective immunity to infection and uncovered a critical role for IL-25 in airways hyperresponsiveness and inflammation. We developed a unique monoclonal antibody that blocks the interaction of IL-25 with its receptor, and administration of this antibody prevents airways hyperresponsiveness in a mouse model of allergic asthma. Importantly, since the anti-IL-25 antibody cross-reacts with human IL-25, blocking its interaction with the human IL-25 receptor, we have humanised this antibody in collaboration with MRC Technology, and are continuiing to validate this molecule in asthma models. It is becoming increasingly clear that innate immune cell types, in addition to the classical Th2 cells, can produce type-2 cytokines and that they may play critical roles in the initiation of the type-2 response. Using Il13-eGFP reporter mice, we discovered type-2 innate lymphoid cells (ILC2) and demonstrated that they are the predominant early source of the IL-13 critical for inducing expulsion of the helminth parasite, Nippostrongylus brasiliensis, following infection. ILC2 also expand in experimental models of asthma, where they represent an important source of type-2 cytokines. Our recent studies have indicated that ILC2 interact with dendritic cells and Th2 cells to potentiate type-2 immunity. We have shown that these type-2 ILCs develop from common lymphoid progenitors under signals from IL-7 and IL-33 and Notch. We have gone on to show that the transcription factors ROR, a relative of ROR t, and Bcl11b play important roles in ILC2 development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: Adjunct antibody therapy for severe antibiotic-resistant Acinetobacter baumannii infections
Funder: Medical Research Council

Abstract: Acinetobacter baumannii is a major cause of severe infections in Asian LMICs and has high levels of resistance to multiple antibiotics. To counter the threat of A. baumannii infections in LMICs will require the rapid introduction of new therapies which don't stimulate antibiotic resistance. To address this need we will develop an adjunct multivalent antibody therapy against protein antigens to promote A. baumannii clearance and improve antibiotic efficacy. We will use our recent A. baumannii genome data for 232 strains isolated from Thai patients to construct a comprehensive protein microarray of conserved proteins. This will be probed with sera from Thai subjects recovering from A. baumannii infection and from mice exposed to non-fatal A. baumannii infection to identify antigenic proteins. RNAseq of bacteria recovered from mouse and ex-vivo blood models of infection will identify A. baumannii proteins that are highly expressed during infection and in response to antibiotics and therefore are suitable targets for an antibody therapy. From these data, we will select protein antigens for testing as targets for antibody therapy using in vitro immune assays and mouse models of A. baumannii infection. The most effective antigens will be combined for a multivalent antibody therapy. To better define the role of adjunct antibody therapy we will prospectively collect clinical data on 100 Thai patients with proven A. baumannii infection. In addition, we will purify from these subjects antibody the above data demonstrate are effective at controlling A. baumannii infection for efficacy and dose response testing using a human blood infection model. Overall, the project will develop a novel antibody adjunct therapy for use in severe A. baumannii infections in LMICs that can help combat antibiotic resistance, and provide the clinical and in vitro proof of principle data important for further clinical development of the therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: "The role of extracellular vesicle miRNAs in Mesenchymal Stem Cells' effects on macrophage modulation in ARDS"
Funder: Medical Research Council

Abstract: Acute Respiratory Distress Syndrome (ARDS) is a major cause of acute respiratory failure in critically ill patients, with no effective treatment. We have demonstrated that Mesenchymal Stem/Stromal Cells (MSCs) hold significant therapeutic promise for this condition. MSCs are rapidly progressing to clinical trials across the world, and we will shortly commence phase I/II clinical trial of MSCs in ARDS under a Wellcome Trust funding. The major challenge for rational development of MSC-based therapy is the lack of clear understanding of mechanisms of MSC action in the inflammatory environment, which poses a roadblock for clinical translation. Regulatory bodies highlight the need for evidence of therapeutic mechanism of action to be incorporated into clinical MSC Investigation Medicinal Product Dossiers. This knowledge is critical for the rational development of MSC-based therapies to ensure maximum realisation of their therapeutic potential. In this project, we will investigate immunomodulatory mechanisms of MSCs mediated by miRNAs secreted in the MSC-derived extracellular vesicles using clinically relevant in vitro and in vivo models of ARDS and clinical samples of ARDS patients who has recieved MSCs as a treatment. The anticipated output is an understanding of the specific mechanisms of the immunomodulatory action for MSC cell therapy and MSC extracellular vesicles in ARDS thus enhancing the potential of translation into the clinic. Results from these studies will be timely to inform the design of the subsequent phase III trials and phase I/II trials for MSC extracellular vesicles. miRNAs found to be functionally important may be exploited therapeutically independently of MSCs. The results from these studies may also have relevance for other inflammatory conditions


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: UKRMP/Immunology: Defining the role of tissue-resident immune cells in alveolar epithelial cell regeneration
Funder: Medical Research Council

Abstract: The goal of our research is to understand the contribution of tissue-resident immune cells (TRICs) to regeneration of an injured alveolar epithelium. Intense work is ongoing to examine the role of stroma and mesenchymal cells but very little is known on how immune cells maintain self-renewal during homeostasis and promote regeneration after injury. We will use a multi-faceted but cohesive approach as follows: (i) immune cells including TRICs are mapped to regenerating alveolar epithelium in human idiopathic pulmonary fibrosis lungs (a disease of aberrant alveolar regeneration) to determine the types of TRICs that colocalise to normal and aberrant alveolar regeneration in human lungs (ii) types, frequency, function and signalling pathways of TRICs are interrogated at injury, repair and regeneration or fibrosis time points in murine model of injury and appropriate regeneration compared to injury with fibrosis and (iii) test the hypothesis that a subset of regulatory T cells, Jag1+ Tregs, interact with CD103+ dendritic cells via Jag-Notch signalling to enable regeneration of type II alveolar epithelial cells after injury. These studies will complement each other and provide a detailed and robust examination of the immune cells in the regenerating alveolar niche in human lungs, ex vivo lung models and murine models. We will use advanced technology to aid of quest, including tissue and cell CYTOF, multi-colour high resolution immune-profiling, single-cell RNA sequencing, crispr-Cas9 gene-editing and judicious use of targeted genetically engineered murine models including the high definition confetti-reporter technology for lineage tracking.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: Defining pathogenic B cell regulation and role in scleroderma-associated interstitial lung disease (SSc-ILD)
Funder: Medical Research Council

Abstract: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) has significant mortality of up to 50% and early development of lung fibrosis is associated with aggressive clinical course. SSc-ILD is strongly associated with levels and specificity of autoantibodies and mediators expressed by B cells. However, current biologic therapies targeting B cells appear to benefit only a proportion of patients. The two collaborating centres recently discovered subsets of autoreactive IL-6-producing transitional B cells likely to initiate and SSc sustain disease processes. My proposal will analyse the transcriptome and antibody repertoire of circulating B cells from patients with SSc-ILD to identify biomarkers that predict responsiveness pre-treatment with rituximab or tocilizumab. My aims are (1) to undertake detailed retrospective clinical assessments including autoantibody profiling in SSc cohorts in relation to treatment responsiveness to rituximab and tocilizumab. This data will inform patient selection criteria for the remainder of this project. (2) to recruit patients with high risk for progressive ILD for single B cell transcriptome and antibody repertoire analyses before and after treatment. I hope to retrieve 2 patient samples per subgroup (treatment subgroups and non-progressor/progressor subgroups for scRNA-seq). (3) Using scRNA-seq, further characterisation of the repopulating B cells after treatment in relation to patient's clinical response will be undertaken. This may help to identify pathogenic B cells from other healthy B cells in responder compared with non-responder patients. This project will use approaches already established in rheumatoid arthritis and multiple sclerosis to identify pathogenic B cells. This study will define the relevance of subsets of B cells to SSc pathogenesis and facilitate precision medicine with targeted biologic therapies in SSc-ILD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: Investigating the influence of immune cells and mediators on lung extracellular matrix remodelling during asthma.
Funder: Wellcome Trust

Abstract: Asthma is a chronic inflammatory disorder of the lungs which causes the airways to temporarily narrow in response to specific triggers. Narrowing can usually be relieved using an inhaler but there are multiple long-term impacts of asthma. Alongside chronic inflammation, asthma is also characterised by airway remodelling. Airway remodelling is a process whereby structural tissue cells make excessive matrix proteins (e.g. collagen) leaving the lung stiff, less elastic and with reduced function. Current treatments fail to reverse/prevent these structural lung changes from occurring in asthma. I aim to learn more about lung remodelling in asthma and how it is regulated. Initially, I will investigate the different types of matrix changes in the lungs tissue from people with asthma and see whether any changes are associated with any specific types of inflammation. I will also use a mouse model of airway remodelling to examine how remodelling is initiated and whether inhibiting inflammation or specific molecules that are increased in asthma, prevents remodelling from developing. Overall, this project will help us understand how the matrix changes in the lungs during remodelling and will help identify the cells or molecules that could be targeted therapeutically to prevent or reverse lung remodelling in asthma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: Governance of anti-fungal immunity by the pulmonary tissue environment
Funder: Wellcome Trust

Abstract: Aspergillus fumigatus (Af) fungal spores, abundant in the environment, are a major cause of asthma. Asthma is a broad disease, not just a type-2 eosinophil dominated disorder, with a crucial involvement of type-17 related neutrophil recruitment. However, the key innate immune cells (dendritic cells (DCs) and macrophages) that dictate this balance to anti-Af are unknown. The lung airways are another crucial yet underappreciated aspect, which I have found governs innate cell responses via modification of their metabolism. Compared to other mucosal sites the lung airways have distinct profiles of nutrients and mucus, but it is unknown whether these regulate innate cell induction of anti-fungal allergy. Here, I will define the DC and macrophage subsets that mediate type-2 vs type-17 anti-Af responses. I will identify if anti-Af allergy alters airway nutrients and/or extracellular factors, exploring if this controls innate cell anti-Af responses via altering cellular metabolism. Additionally, I will identify the critical fungal spore motifs that, along with environmental factors, induce innate cells to mediate anti-Af allergy. Together, this proposal will determine how lung nutrients and extracellular host/fungal factors cause DCs and macrophages to induce anti-Af allergic responses, enabling future design of novel strategies to treat asthma and fungal lung disease.

Lay abstract: Our lungs are exposed to thousands of fungal spores everyday (particularly Aspergillus), triggering immune cells in the lung to cause asthma and severe allergic disease. Despite the rising number of cases and developing resistance to current therapies, we do not understand how or why Aspergillus causes asthma. Furthermore, I have discovered that the lung airways govern immune cell responses via modifying their metabolic state. Yet the airway factors that modify immune cell metabolism to cause asthma are unknown. I aim to understand how specialised immune cells, called dendritic cells and macrophages, cause asthma when responding to Aspergillus. I will pinpoint the specific cell subsets, establish how the airway environment governs their ability, and define the precise fungal motifs these cells recognise to mediate allergic inflammation. Overall, my project will discover how fungal asthma develops, as well as reveal new treatment strategies to prevent and/or treat these conditions in the future.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY
Title: Defining the innate-like mucosal T cell response to bacterial infection in airways disease
Funder: Wellcome Trust

Abstract: Exacerbations cause most morbidity, mortality and economic costs of asthma. Most are driven by infections and constitute a significant unmet clinical need, particularly in non-eosinophilic disease. The 2017 AMAZES trial showed azithromycin reduced exacerbations in severe asthma, but raises several critical questions, especially, the relevant mechanisms of action, whether anti-microbial, anti-inflammatory or immunomodulatory, remain unknown. AIMS 1.To discover the mechanisms of macrolide activity in neutrophilic asthma. 2.To define how non-typeable Haemophilus influenzae (NTHi) establishes a niche in neutrophilic airways. 3.To explore the role of mucosal associated invariant T (MAIT) cells and their ligands in infection and asthma. OBJECTIVES 1.In vitro modelling of bacteria/epithelial/immune cell interactions in NTHi-infected human airway epithelium at air-liquid interface. 2.Murine modelling of mucosal immune responses to NTHi and effects of azithromycin on pulmonary inflammation in vivo. 3.Characterisation of human airway cellular immunology and microbiology using bronchoscopy before and after azithromycin therapy to confirm the human relevance of these pathways in asthmatics with/without bacterial airway infection. This work will i) elucidate the basic immunology of host-pathogen interactions and MAIT-cell biology; ii) identify mechanisms and biomarkers key to informing and refining future human clinical trials of macrolides in airways diseases; and iii) explore the therapeutic potential of MAIT-cells.

Lay abstract: Asthma affects > 350 million people globally, inflicting morbidity, mortality and massive economic costs, predominantly from infections which exacerbate airways inflammation. Long-term macrolide antibiotics reduce exacerbations but exactly how is unknown. Furthermore, macrolide use risks inducing antimicrobial resistance. I aim to elucidate how macrolides prevent exacerbations and explore the role of airway mucosal associated invariant T (MAIT)-cells using three approaches. We will infect human airway samples in the lab. We will study long-term Haemophilus infections and synthetic MAIT-cell ligands in susceptible mice. We will then confirm these findings in humans using bronchoscopies in volunteers with asthma receiving macrolides. These studies are essential to define who should receive macrolides, and identify alternative therapies, which could reserve these essential medicines for other uses. If boosting MAIT-cells with synthetic ligands is effective, this could lead to development of improved vaccines for a wide range of lung infections, which cause 6% of global human disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY;INFECTION
Title: The role of innate immunity in respiratory viral infection in the elderly
Funder: Wellcome Trust

Abstract: With age, there is a decline in immune function, which renders the elderly particularly susceptible to lung infections, such as respiratory syncytial virus (RSV). During ageing there are also significant changes to cellular metabolism. Recent discoveries have shown that the function of cells of the immune system is profoundly influenced by their metabolism. We hypothesise that differences in the immune response to lung infection in the elderly are the results of age-related metabolic changes. In this project we will specifically study age-related changes in alveolar macrophages (AM), immune cells that are an important first line of defence against lung infection. We will compare AM responses to infection in young and elderly mice. Next, we will evaluate differences in metabolic pathways in these cells. If metabolic differences are detected, we will aim to restore macrophage responses to infection in the elderly by manipulating their metabolism. In addition, we will ask whether transfer of AM from young to elderly mice will protect against infection. The global population is ageing and lung infection is a growing health burden worldwide. In the long term this project may identify new targets for treatment and/or prevention of severe lung infections in the elderly.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY;INFECTION
Title: Flow cytometric isolation and characterisation of cells from human lung samples
Funder: Wellcome Trust

Abstract: Presently, there is no cell sorter available at the Royal Brompton Campus of the NHLI, Imperial College London. The lack of this piece of equipment is seriously curtailing research at this site. An example of this is the identification of a specific macrophage phenotype in the lungs of patients with chronic obstructive pulmonary disease (COPD) (Chana et al JACI 2014) that is highly proinflammatory but fail to clear baterial pathogens (Taylor et al, ERJ 2010), apoptotic cells and fungi. We have identified these cells using flow cytometry and confocal microscopy, and can show differences in cell surface regulation of specific receptors (see appendix 1), but we cannot take functional characterisation of these cells further without a cell sorter. There are a number of other research groups whose work is also seriously hampered and the Clinical Research Facility at the Royal Brompton Hospital has rejected studies because of lack of a sorter. To this end, we request funding for a BD FACSARIA III multicolour cell sorter within a biosafety cabinet. This would not only allow for isolation of specific cell populations, but also allow for culture of these cells for future functional studies.

Lay abstract: One person dies every five minutes in the UK from a lung condition. There are many different lung diseases and we want to understanding why they occur and how we can treat them. To do this, we take samples directly from patients and healthy people and look for differences so we can find new medicines. Samples from people are limited and therefore, we need to be precise about the types of cells use, therefore we are request funding for equipment that ‘sorts’ specific types of cells. For example, in chronic obstructive pulmonary disease, white cells in the lung called macrophages, are less able to remove bacteria. However, not all macrophages have this defect. We want to separate those that ‘eat’ from those that do not by ‘feeding’ them fluorescently-labelled bacteria. We can then see what is different about these cells and improve removal of bacteria and reduce chest infections.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY;INFECTION