NIHRDataInsights/HRCSData huggingface dataset:
Title: Spatial (dis-)organisation of lipid metabolism in chronic liver disease and cancer
Funder: Medical Research Council

Abstract: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of lipids in the liver, however a subgroup of patients will progress to more serious conditions, including nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Currently, the driver for this progression is not fully understood, particularly with respect to the metabolic adaptions in liver cells, which lead to hepatocellular injury, fibrosis and cancer. Given that NAFLD is expected to become the main cause for patients requiring a liver transplant, there is an urgent need for novel tools and approaches to better understand changing liver physiology during injury, fibrosis and cancer. Understanding cells in their morphological context is critical to understand their function. Here we will use mass spectrometry imaging and lipidomics to study spatially-resolved metabolic adaptive changes during chronic liver disease, using animal models of fibrosis and clinical samples (Aim 1). Chronic liver disease is a major risk factor for HCC. We will study the metabolic heterogeneity of tumours in a large cohort of HCC patients for improved patient stratification and link lipid profiles in tissue to blood, to form the basis for a non-invasive diagnostic test (Aim 2). Finally, we will develop a transformative strategy that combines innovative mass spectrometry experiments with multiplex imaging of proteins and sophisticated machine-learning tools to investigate modulation of immunometabolism and inter-cellular cross-talk in chronic liver disease and HCC (Aim 3). The outcome of this research will be to shed light on the complex processes governing the organisation and regulation of metabolism during liver fibrosis and carcinogenesis, identify candidate molecular markers for patient stratification and reveal metabolic vulnerabilities that can be targeted therapeutically, leading to improved patient outcome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE
Title: 2018 Doctoral Fellowship: Developing an ICU swallowing intervention to improve outcomes following prolonged intubation in cardiac surgical patients: a feasibility study
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Background: Swallowing difficulties following critical illness are common. Prevalence rates for dysphagia following prolonged intubation vary from 20%-67%, with incidence in cardiac surgery patients between 51-67%. Interventions aimed at preventing or minimising dysphagia could reduce long term sequalae including pneumonia, reintubation, delayed return to oral intake and longer length of intensive care unit (ICU) and hospital stay. The average cost of an ICU bed in the UK is £1800 per day. A swallowing intervention that minimises or prevents dysphagia would decrease NHS costs, shorten duration of hospital stay and result in better outcomes for patients. Aim: To develop and test the feasibility of a swallowing intervention that could be delivered within the ICU to prevent or minimise dysphagia in post-operative cardiac surgical patients in cardiac surgical ICU. Methods: This study will use a range of mixed methods. 1. A systematic review will be conducted to synthesise the evidence on swallowing interventions delivered within the ICU. 2. A panel of experts on treating patients with dysphagia will be convened to review the evidence and reach consensus on an intervention that could be delivered within the ICU. 3. Focus groups with patients who have experienced dysphagia following cardiac surgery and their families, critical care speech and language therapists and members of the multidisciplinary ICU team will be conducted to obtain views on the feasibility and acceptability of the intervention. 4 A feasibility study will be conducted in a single centre cardiac surgical ICU to test intervention delivery, recruitment rates and outcomes. Benefits: This study will show if the application of an ICU intervention for preventing dysphagia in cardiac surgical intensive care is feasible in a UK ICU environment. It will inform the design of a large clinical trial powered to detect differences in clinically relevant outcomes when compared with standard care.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: ORAL AND GASTROINTESTINAL;CARDIOVASCULAR
Title: Mechanisms controlling hepatoblast specification during human development
Funder: Wellcome Trust

Abstract: The liver is responsible for a plethora of vital functions within the body. Despite the importance of this organ, the mechanisms controlling liver development are poorly understood especially in humans. This knowledge gap not only represents a challenge for the development of new therapies against liver diseases but also a key limitation to establish protocols for producing liver cells in vitro. Therefore, new systems to model and understand human liver development are urgently needed. My project aims to understand the mechanisms which drive specification of the liver bud which represents the first stage of liver development. Specifically, I aim to define the function of key signalling pathways controlling human liver bud induction and develop a new platform to model human foregut development. By performing various high-throughput analyses, I will also investigate the regulatory mechanisms with which Activin/Nodal promotes commitment to liver fate whilst concomitantly preventing specification towards pancreatic fate. Finally, I plan to use newly-derived liver bud progenitors to generate hepatoblast organoids which closely resemble their in vivo counterpart. If successful, this work would not only enhance our understanding of liver development, but could also contribute to the development of novel regenerative approaches for the treatment of liver disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL;GENERIC HEALTH RELEVANCE
Title: Infants with intestinal failure. Establishing an ethical framework for an emerging therapy
Funder: Wellcome Trust

Abstract: This project will establish a practical ethical framework for decision-making in neonatal intestinal failure (IF). It aims to identify circumstances in which active therapy might be ethically obligatory, circumstances in which it may only be ethically appropriate to recommend palliative care, and situations in which active treatment is ethically acceptable but not obligatory This will be achieved by combining empirical research with normative analysis and reasoning using a four stage process as described below: • A critical interpretive review of empirical and theoretical literature will be carried out in order to acquire a thorough understanding of the clinical and ethical factors likely to be relevant. • Qualitative methodology (semi-structured interviews with thematic analysis) will then be employed to develop a contextualised understanding of the problem as experienced and understood by a range of stakeholders including a healthcare professionals from different subspecialties, families and children. • Coherence will then be sought between the empirical data and normative theory using reflexive balancing to reach defensible normative conclusions. • Finally a draft guidance framework will be developed through a structured online consensus method (DELPHI) in order to gain consensus amongst professionals to develop a usable ethical framework for decision making in neonatal IF.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: ORAL AND GASTROINTESTINAL;GENERIC HEALTH RELEVANCE
Title: Cellular mechanisms of metabolic sensing by human hypothalamic neurons
Funder: Wellcome Trust

Abstract: Obesity is a major public health problem, but its molecular mechanisms are poorly understood, frustrating efforts to develop broadly effective treatments. Obesity is characterised by abnormal energy homeostasis, which is regulated in large part by hypothalamic melanocortin neurons. The activity of melanocortin neurons is in turn regulated by circulating nutrients and hormones (e.g. leptin), but the mechanisms by which they sense and integrate these metabolic signals have been difficult to study using traditional model systems. Functional human melanocortin neurons derived from pluripotent stem cells provide an unprecedented opportunity to illuminate and therapeutically harness the molecular mechanisms by which human melanocortin neurons sense metabolic signals to regulate energy homeostasis. In particular, they enable a detailed characterisation of leptin signalling and direct testing of hypothesised mechanisms of leptin resistance. At a cellular level, the role of primary cilia in sensing and integrating leptin and other metabolic signals can be studied. Third, the synergistic action of different metabolic signals in vitro will be used to predict effective anti-obesity therapies in vivo. Together these studies will shed light on obesity disease mechanisms and facilitate the development of effective anti-obesity treatments.

Lay abstract: Obesity is a major public health problem lacking broadly effective treatments. To develop such treatments, I will study the cell types in the brain that regulate appetite. To do so, I developed a method to generate large numbers of functional human appetite-regulating brain cells in a culture dish from stem cells. Like their counterparts in the brain, these brain cells sense and respond to metabolic signals, including nutrients and hormones such as leptin. I will explore how defects in leptin signalling might lead to obesity, how these brain cells sense metabolic signals and integrate them using specialised "sensory antennae", and ask which combinations of anti-obesity drugs act on human appetite-regulating brain cells in culture and might therefore be effective at promoting weight loss in mice. Together these studies will shed light on the cause of obesity and facilitate the development of effective anti-obesity treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;GENERIC HEALTH RELEVANCE;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;CANCER AND NEOPLASMS
Title: Engineering the microbiome to expose the functional biogeography of the gut
Funder: Wellcome Trust

Abstract: The mammalian gut microbiome plays a critical, but poorly understood, role in the triggering, maintenance and response to inflammatory disorders including inflammatory bowel disease and colorectal cancer. Dynamics in microbial function throughout the gut, whether caused by fluctuations in microbial abundance or gene expression, are likely to play an important role in disease. However, a lack of methods to study microbial function in the context of the gut's varying longitudinal and radial microenvironments has hindered our understanding of the extent and importance of this factor to disease severity. My laboratory will engage the power of synthetic biology to create sophisticated bacterial probes, screening for new disease-specific bacterial biomarkers and creating complex synthetic circuitry to afford bacteria spatially-selective, non-invasive, disease monitoring capabilities. Combining these engineered biosensors with advanced imaging of bacterial localisation and function in the context of the three-dimensional tissue architecture, and with next-generation metagenomic and metatranscriptomic sequencing techniques, I will comprehensively investigate the functional biogeography of the gut under healthy and inflamed conditions. Harnessing this knowledge, we could develop new diagnostics and treatments for diseases that collectively have a profound impact on global human health.

Lay abstract: The human gut houses a dense population of microbes that profoundly influence our health. This microbiome has been linked to susceptibility to a wide range of diseases including inflammatory bowel disease, cancer and even mental health problems. For this reason, the gut microbiome is a highly attractive target for use in clinical applications. However, many important details remain poorly understood. Gut bacteria themselves are ideally situated to eavesdrop on their surroundings. Using synthetic biology approaches, my laboratory will therefore engineer bacteria to sense and record information about disease while traveling through the gut. Using these engineered tools, combined with advanced methods to visualize and probe bacteria inside the gut, we will investigate how the microbiome varies in its function at different locations throughout the gut. Harnessing this knowledge, could help us to develop new diagnostics and treatments for diseases that collectively have a profound impact on global human health.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL;GENERIC HEALTH RELEVANCE;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploiting Microbial Modulation of Commensal Communities to Prevent the Onset of Colitis
Funder: Wellcome Trust

Abstract: The microbes that colonise the gastrointestinal tract are collectively referred to as the gut microbiome. Although our understanding of the microbiome is limited, its role in disease is becoming increasingly apparent. In inflammatory bowel diseases (IBDs), intestinal inflammation (colitis) is associated with the expansion of Enterobacteriaceae species. Work in mouse models of IBD has shown that: i) tungstate ameliorates pathology by inhibiting the growth of Escherichia coli and other, undefined Enterobacteriaceae; and ii) non-Enterobacteriaceae microbiome members upregulate tungstate transporter expression prior to the onset of colitis. Thus, we hypothesise that a microbiome-driven reduction in tungstate availability may dictate the development of Enterobacteriaceae-driven colitis. We will first examine the effects of tungstate on the growth of Citrobacter rodentium and Blautia coccoides, model Enterobacteriaceae and tungstate regulator species, respectively. We will then manipulate the ability of B. coccoides to uptake tungstate through direct, microbial manipulation and indirect, dietary intervention. We will employ next generation sequencing of a model microbiome alongside immunological analysis to accurately define tungstate-driven microbial responses which lead to the development of colitis in vivo. Our work will aid our understanding of the microbiome and its role in IBDs, ultimately taking a translationally relevant approach to direct disease outcome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFECTION
Title: Understanding the interaction between human milk oligosaccharides and the gut microbiome in preterm infant health and disease
Funder: Wellcome Trust

Abstract: Necrotising enterocolitis (NEC) is a leading cause of death in babies born extremely preterm. NEC infants generally have increased gram-negative bacteria compared to matched controls, potentially resulting in an LPS-stimulated increase in TLR4 and inflammatory cytokines in the intestinal epithelium, ultimately leading to the breakdown of epithelial integrity and necrosis. My recent work has shown that human milk oligosaccharides (HMOs) promote the establishment of a protective microbiome in the infant gut, which is associated with reduced risk of NEC. This project will identify specific HMOs and bacteria that promote gut health and reduce NEC in preterm infants. The project will take advantage of a host-microbe model system I have recently developed. This will provide new insights into NEC pathogenesis, potentially leading to the development or refinement of therapeutics. I will achieve this by answering four critical questions: 1. What specific HMOs and microbial species are associated with NEC or gut health? 2. Do HMOs directly influence the epithelial integrity and inflammation observed in NEC? 3. How do specific bacterial species interact with the preterm intestinal epithelium? 4. Can a combination of HMO (prebiotic) and bacteria (probiotic) promote gut health and protect against NEC?

Lay abstract: Babies born very preterm are immature and have abnormal bacterial colonisation of the gut, placing them at significant risk of life-threatening disease. Maternal breast milk contains sugars (prebiotics) that cannot be digested by humans and are instead used by beneficial bacteria (probiotics) to grow inside the baby’s gut. Together, the combination of breast milk sugars and bacteria that live inside the gut can contribute to protection from disease. However, the exact sugars and bacteria, as well as the process by which they provide protection, has not been defined. I will determine this using maternal and preterm infant samples, alongside models I have developed for studying the preterm gut. My work will shed new light on how the preterm gut can be modified to promote health. The sugars and bacteria which promote health may refine clinical practise or provide optimal targets for the development of therapeutics for preterm infants.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFECTION
Title: Investigating signalling pathways in intraepithelial lymphocytes (IEL) in the small intestine
Funder: Wellcome Trust

Abstract: Intraepithelial lymphocytes (IEL) are T cells that reside interspersed between intestinal epithelial cells in the gut. They provide protection to the gut by coordinating immune responses towards pathogens and producing factors which maintain the gut epithelial barrier. However, dysregulated IEL function has been associated with increased gut inflammation promoting inflammatory diseases of the gut including coeliac disease and inflammatory bowel disease. The signals which activate IEL and the intracellular machinery used to communicate these signals to have an effect within the cell are relatively unknown. I propose to investigate the signalling pathways in IEL using techniques such as flow cytometry, mass spectrometry and RNA sequencing. I will stimulate IEL through cell surface receptors to initiate the downstream signalling events. I will compare the IEL response to stimulation with conventional T cell responses to determine similarities and differences in IEL signalling. I will look at proteins which have become phosphorylated upon stimulation and, using a RiboTag mouse, detect which proteins are translated as a result of the activation. I will also investigate IEL signalling in vivo. These studies will increase understanding of how IEL become activated and offer opportunities to manipulate these pathways in the treatment of disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of enteropathy and systemic inflammation in severe acute malnutrition
Funder: Wellcome Trust

Abstract: Being extremely underweight from lack of nutrition can lead to a condition called severe acute malnutrition (SAM). This can cause a number of problems including leaving children with thin and leaky guts. Children with SAM have a high chance of dying during hospital admission, and during the following year. The cause of this ongoing risk of death is unknown, but may be related to the changes in the child’s intestines which can result in the immune system not working properly, including not being able to fight off new infections. From stored samples of a completed study of 200 children with SAM, I will look at different markers in the blood and stool to see how well the gut and the immune system are working, and see if these markers relate to the chances of the child dying or being readmitted to hospital in the following year. After this I will look at some of these markers in a new trial that is looking at new medicines to improve the health of the gut in children with SAM. I will see if it also improves the markers of the immune system.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Innate lymphoid cells; promoting homeostasis and preventing gut dysbiosis
Funder: Wellcome Trust

Abstract: I propose to examine the hypothesis that innate lymphoid cells (ILCs) mediate crosstalk between the intestinal microbiota and the reconstituting adaptive immune system in a cohort of children with primary immunodeficiency disorders undergoing haematopoietic stem cell transplantation (HSCT). I will use mass cytometry to examine the reconstitution of leukocyte populations after HSCT in a longitudinal fashion. I will characterise the peripheral blood ILC compartment in detail, including expression of activation markers, chemokine receptors and cytokines by ILC subsets ex vivo. I will measure gut bacterial diversity in longitudinally collected faecal samples and assess markers of microbial translocation. These immune and microbial parameters will be correlated with clinical features in a multi-dimensional statistical model to identify risk factors for HSCT outcomes such as graft-versus-host disease (GVHD) and gut failure. Further analysis of ILC function will be performed through in vitro studies of these immune populations to examine how they can regulate T cell responses. The impact of microbial signals and cytokines on ILC regulation of T cells will be assessed. A better understanding of ILC function in the context of immunodeficiency and HSCT may help us to develop strategies to avoid immune complications such as GVHD in some transplant recipients.

Lay abstract: I propose to study a group of children with rare genetic disorders of the immune system where the only cure is haematopoietic stem-cell transplant. A serious complication of this is graft-versus-host disease (GVHD), in which the transplanted immune cells attack the host’s organs, particularly the bowel. Innate lymphoid cells (ILCs) are a small proportion of white blood cells that are important in protecting barrier surfaces including the gut from bacterial invasion. My key goals are to identify whether ILCs also have a role in mediating signals between bacteria in the gut and other immune cells. By exploring this process I hope to better understand how dysregulated immune cells can drive immune complications in transplant recipients. To achieve this I will determine whether ILCs differ in their characteristics between children who experience a complicated or a smooth transplant course. I will correlate the levels of “good” and “bad” bacteria in the gut during transplant with the behaviour of the transplanted immune cells and I will explore whether signals from bacteria can teach ILCs to behave differently towards other immune cells. Through this work I hope to identify how ILCs can be manipulated to treat or prevent human inflammatory diseases.

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