NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploiting hepatocyte and endothelial cell interactions for the development of scalable human liver tissue
Funder: Chief Scientist Office, Scotland

Abstract: Liver disease is the 5th commonest cause of death in the UK. 16,087 people died from liver disease in 2008, a 4.5% increase since 2007 and trends are rising. The only curative option for end-stage and fulminant disease, that meets “Kings College Criteria”, is liver transplantation. However, organ availability cannot meet demand and many patients die waiting for an organ. Those who do receive transplantation require lifelong immunosuppression with increased risks of infection, cancer, renal and cardiovascular disease. As such, there is a clear imperative to provide alternatives to liver transplantation. My proposal focuses on the generation of human liver tissue from pluripotent stem cells and its translation to industry and the clinic. To build and test novel prototype tissue, I have developed an interdisciplinary approach and built a team of researchers and collaborators with expertise in xeno-free cell production, polymer chemistry and tissue engineering. Our preliminary studies suggest that it is feasible to generate 3D liver tissue from research and clinical grade human stem cell lines. I believe with further development the project will deliver an enabling technology, capable of accurately modelling human liver biology “in a dish” and serving as an attractive candidate for cell based therapy.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Characterising a Novel Murine Model of Alcoholic Hepatitis
Funder: Guts UK

Abstract: The goal of this research is to produce a validated mouse model of AH in order to facilitate discovery and testing of therapeutic strategies aimed at reducing the high morbidity and mortality associated with this condition. Through publication and presentation of my results at conferences, I aim to disseminate the findings to academics, clinicians and the general public as a pathway to impact.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Ghrelin mediated lipid retention and insulin resistance in human visceral adipose tissue
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Abdominal fat is important in type 2 diabetes. Biologically, fat is “very active” and is able to make different chemicals and hormones that affect the way in which the body deals with glucose and insulin. When this becomes abnormal, type 2 diabetes may develop. The aim of this studentship is to look at the role that a gut hormone called ghrelin has in influencing fat behaviour and the risk of type 2 diabetes. Our previous work within mice shows that ghrelin increases abdominal fat. We have also shown that this occurs due to the build-up of cholesterol within the fat cells and that this is encouraged by treatment with ghrelin. We will examine how ghrelin influences the behaviour, chemistry and genetic function of fat cells obtained from humans. The proposed work will therefore develop our previous research performed in mice. We will use fat samples obtained at the time of operations from lean, obese and obese patients with type 2 diabetes. Scientific methods of analysis established in our laboratory will be used to examine protein and gene function within the samples. The studentship will enable us to:- a) Gain a better understanding of the cause of obesity and type 2 diabetes with particular focus on ghrelin. b) Develop studies to look at the role of ghrelin mediated cholesterol build-up in fat and how this is related to type 2 diabetes. Further work may lead to the identification of new molecules as potential treatments in type 2 diabetes and obesity. Patients with diabetes have been involved the creating of this studentship application. The proposal also has the support of the Diabetes Research Network in Wales.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.1 INDIVIDUAL CARE NEEDS
Health categories: ORAL AND GASTROINTESTINAL
Title: A novel enzymatic means to confirm correct and safe nasogastric tube placement
Funder: Innovate UK

Abstract: Our pilot study (n= 23, including 15 patients on antacid medications) found this new test was 100, if validated further in this proposed, thorough clinical evaluation and scientific device development programme, mean that the new test would reduce feeding incidents due to misinterpretation of pH strip and X-ray results and cut the need for chest x-rays by about a third. Wider benefits to healthcare providers and patients include 1) significant cost savings (£1 per enzymatic test versus £120 per x-ray); 2) reduced risk of misdiagnosis of misplaced NG tubes; 3) biopsychosocial improvements for patients, 4) greater confidence and reliability in nursing care and 5) improved patient care and safety. Upon validation, there would be clear potential to apply related enzymatic marker detection more broadly to detect disease, health monitoring and infection.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: The Role of Nutrients, Gut Dysfunction and the Gut Microbiome in Determining Health Outcomes in Undernutrition
Funder: Medical Research Council

Abstract: Undernutrition affects 462 million people world-wide with 165 million children being stunted and 52 million wasted. The factors underpinning SAM are complex and multifactorial, ultimately resulting in disruption of the normal gut microbiota,reduced assimilation of vital nutrients, altered gut barrier function, impaired mucosal immunity and increased risk of gram negative bacteraemia which form a vicious cycle. Environmental enteric disease (EED) shares common features of gut dysfunction with SAM including villous atrophy, disruption of the normal gut microbiota, disruption of the gut barrier function, increased local and systemic inflammation and bacterial translocation which adversely affect growth and cognitive development. This programme will bring together leading experts from across the scientific community to investigate how legumes (pulses) can offer a joint solution to the supply of quality protein and fermentable carbohydrate to support a competent diverse gut microbiome and optimum gut barrier function needed in SAM and EED. The focus of this application is to facilitate the development of a substantive multi-disciplinary research programme to enhance the management of malnutrition in LMICs. To achieve this, we will begin with a kick-off meeting at beginning of the project to set a research development agenda in four key areas: 1. Improved assessment of gut barrier dysfunction 2. Fermentable carbohydrate as a solution to gut barrier dysfunction and improving amino acid supply as a method of optimising small intestinal function. 3. Determine the protein requirements of malnourished children under high pathogen burden 4. Legumes as a solution to meeting protein and micronutrient requirements and improved gut barrier function 5. Sustainable intake of legumes Our long-term plan is to develop and refine current recommendations of macronutrient feeding regimens to reduce morbidity and mortality associated with gut barrier dysfunction in LMIC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Improving the survival, growth and developmental of low birth weight newborns through better nutrition
Funder: Medical Research Council

Abstract: We plan to establish a core network of 6 neonatal units (NNUs; 4 Nigeria/2 Kenya) to improve gut health and early nutrition in low birthweight (LBW) infants. LBW results from premature birth, intra-uterine growth retardation or both. Immature gut structure and function in preterm infants compromises nutrition, facilitates sepsis through bacterial translocation and risksnecrotising enterocolitis (NEC). Abnormal microbial colonization of the gut occurs during prolonged NNU admission including with anti-microbial resistant bacteria. Improved gut health and early nutrition would likely prevent sepsis and improve brain and other organ development.A weak evidence base contributes to the variation in practice regarding establishing feeds especially in vLBW infants (<1500g). Nutritional interventions to improve gut health and reduce mortality that have become routine practice in many NNUs in richer countries may be practical, safe and affordable in low-resource settings. An example is probiotics that reduce all-cause mortality in vLBW infants (RR 0.72; 95% CI 0.57-0.92) and prevent NEC stage 2 or greater (0.57; 0.43-0.74). Our network will evaluate current evidence and document variation in feeding practices, adapt core outcome sets for common diseases, share anonymised clinical data and identify priorities for research. The dataset will collect information about maternal and early life variables as a basis for the assessment of long-term growth, respiratory and neurodevelopmental outcomes. We will pilot test volumetric absorptive microsampling technology combined with QPlex. Array for measuring inflammatory markers and micronutrients in small blood samples and high resolution melt based qPCR to describe acquisition of anti-microbial resistance genes in faecal flora. We will also bank samples for future analysis. We will engage other low-resource NNUs and develop processes that can be rolled-out to expand the network as a resource for multicentre clinical trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining The Macrophage-Regulatory T Cell Axis That Promotes Fibrosis Resolution in the Liver
Funder: Medical Research Council

Abstract: Liver fibrosis represents the final common pathway of all chronic liver disease. We have identified that post phagocytic Ly6Cint hepatic macrophages, restorative macrophages (RMo) are essential for the resolution of fibrosis expressing both matrix degrading MMPs 9 and 12 and the hepatic mitogens, TWEAK and IGF-I. Our pilot studies show CD25 Foxp3 Tregs are also essential for fibrosis resolution. We will interrogate the Treg-RMo interaction to investigate the hypothesis that inflammatory macrophages promote the local accumulation of Treg. On withdrawal of the inflammatory stimulus these then create a "critical niche" that promotes the development of the RMo programme and, ultimately, remodelling of fibrosis with matrix degradation and architectural restoration. Using gene knockout and transgenic mice in which Tregs and RMo can be specifically depleted; we will use our CCl4 based model of fibrosis resolution in which individual cell populations can be tracked and where necessary extracted from fibrotic liver. These populations can be characterised and mapped to position and activity/function in situ histologically and in vitro after extraction. In turn these populations can be related to whole organ histology during distinct and predictable stages of fibrogenesis and fibrosis resolution. We will characterise the behavioural interactions of Treg and RMo and the mechanisms by which the antifibrotic Treg is recruited (by inflammatory macrophages) and executes its mode of action (via the RMo). Specific attributes of the RMo (upregulation of MMPs 9, 12, TWEAK and IGF-I) may be augmented by phagocytic activity. We will study the role of phagocytosis of apoptotic debris in the development of the RMo. By manipulating macrophage phagocytic activity and consequent cell signalling we will augment the RMo phenotype and enhance resolution of experimental fibrosis in tissue culture and in vivo models; with specific focus on PPARg signalling as a classic drugable target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: MICA: Illuminating mechanisms regulating the birth, life and death of the myofibroblast to inform the development of antifibrotics for liver disease.
Funder: Medical Research Council

Abstract: The research will employ the following methodologies in order to meet the stated aims and objectives in the "Case for Support". 1. Human primary liver myobroblasts. These cells will be used to determine mechanisms by which epigenetic and transcription pathways influence fibrogenesis. The cells will be isolated from the normal margins of liver tissue resected for the removal of secondary tumours provided by liver surgeons (Profs White and Mannas) at the Newcastle NHS Trust Freeman Hospital. Isolated cells will be purified by density centrifugation and cultured in serum-containing media. 2. A human myofibroblast cell line, LX2, will be used where high numbers of myofibroblasts are required for detailed studies such as chromatin immunoprecipitation, or where there is a need to modulate the expression of genes under study by transfection-based approaches. The LX2 line was generated in the laboratory of Prof Scott Friedman and is highly representative of the fibrogenic phenotype of primary liver myofibroblasts. 3. Archived paraffin-embedded diseased human liver tissue will be used for immunohistochemical detection of key regulatory proteins identified during the research as important to validate in human diseased tissue. The tissue is managed by the Newcastle University and NHS Trust Biobank and will be supplied as anonymised liver slide sections, with the original tissue blocks being retained by the Biobank. 4. Genetically modified mice (C57/Bl6) for key fibrogenic regulators such as MeCP2 and JunD will be used for supply of myofibroblasts in which these genes are either deleted or mutated into functionally attenuated forms, these studies enabling gene function to be examined with a high degree of confidence. The mice will also be employed in animal models of liver disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: MICA: Clinical development of erythrocyte encapsulated thymidine phosphorylase - a therapy for mitochondrial neurogastrointestinal encephalomyopathy
Funder: Medical Research Council

Abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive metabolic disorder caused by a deficiency in thymidine phosphorylase, which leads to a pathological accumulation of thymidine and deoxyuridine. The disease is relentlessly progressive, and patients die at an average age of 37.6 years. Allogeneic haematopoietic stem cell transplantation (HSCT) offers a potential cure, but carries a high mortality risk. Most patients are ineligible for HSCT due to the current restriction to those without irreversible end-stage disease and with an optimally matched donor. Thus there is a critical requirement to develop an alternative treatment. Our aim is to obtain marketing authorization for our orphan designated enzyme replacement therapy, erythrocyte encapsulated thymidine phosphorylase (EE-TP). In this approach the deficient enzyme is encapsulated within the patient's own erythrocytes in vitro which are then returned to the patient enabling the elimination of the pathological plasma metabolites. A pre- Good Manufacturing Practice (GMP) compliant manufacturing process for thymidine phosphorylase has been established, and Good Laboratory Practice (GLP) pre-clinical studies of EE-TP have revealed no potential serious toxicities that would preclude the clinical use of EE-TP. Clinical compassionate studies of EE-TP in two patients have demonstrated clinical and biochemical benefit. This project will be conducted in three phases: 1) establishing and validating essential processes required for meeting regulatory requirements for operating the clinical phase of this project; 2) conducting a multi-centre (pan European), open-label, multiple ascending dose, Phase II trial in 10 patients with MNGIE, over 36 months; 3) clinical data analysis, dissemination of study results and assembly of regulatory documentation to support the safety, tolerability and efficacy of EE-TP in the treatment of MNGIE for marketing authorization.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Stratified Medicine in Primary Biliary Cirrhosis (PBC): Understanding Disease Mechanisms and Targeting Therapies (UK-PBC)
Funder: Medical Research Council

Abstract: Primary biliary cirrhosis (PBC) is the commonest autoimmune liver disease and a significant cause of morbidity and mortality. Ursodeoxycholic acid (UDCA), the only licensed therapy, slows progression to cirrhosis, but response is inadequate or absent in around 30% of patients, with non-responders facing a 5-fold increased risk of death or need for liver transplant. There is substantial industry interest in novel approaches to treating UDCA non-responders, but little information is available regarding mechanisms underpinning failure to respond to UDCA precluding informed decision making about which agents to take to clinical trial as second-line therapies. We will further develop the 5000 person UK-PBC patient cohort, the largest and best characterised in the world, by targetting recruitment of existing UDCA non-responding patients, and those at high risk of future non-response (for reasons of age), and will utilise it to explore the mechanisms of UDCA non-response. We will work with our industrial and patient-group partners to develop and deliver innovative clinical trials of stratified therapy, and will explore structured approaches to the future delivery of care nationally in PBC. The multi-disciplinary UK-PBC research consortium (www.UK-PBC.com) is fully established and has published landmark clinical and mechanistic studies. A multi-strand approach will be used in which patients will be recruited, pheno-, sero- and genotyped and stratified for UDCA response. A nested cohort of highly informative high-risk/non-responding patients will undergo more detailed cell- & tissue-based study with correlation of biological and clinical outcomes. Mechanistic themes addressing the core pathological processes in PBC will be able to access informative patients to undertake studies aimed at addressing the mechanisms and markers of non-response and identifying optimal therapeutic approaches. Our goal is to move to targeted clinical intervention by the end of the funding period.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: ORAL AND GASTROINTESTINAL
Title: Manipulation of niche signals to advance cell therapies for liver disease
Funder: Medical Research Council

Abstract: My objectives and overall strategy are to understand the mechanisms that regulate maturation, proliferation and survival of hiPSC derived and adult human hepatocytes through: (1) An understanding of hepatic tissue niches reconstructed using high throughout screening platforms (niche microarrays and small molecules) (2) An understanding of more complicated 3-Dimensional hepatic niches reconstructed using engineered multi-celluar PEG scaffolds and a small animal bioreactor. To push towards a therapeutic goal, we will utilise the information gained from sections (1) and (2) with understanding of the abnormal niche created as a result of liver damage, to try and engineer a hybrid "cell - scaffold", which allows transplanted cells to become 'curative' when given to patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: The UK Inflammatory Bowel Disease Bioresource: Progressing from Genetics to Function and Clinical Translation in Crohn's Disease & Ulcerative Colitis
Funder: Medical Research Council

Abstract: Our main objective is to establish a centralised national Inflammatory Bowel Disease (IBD) Bioresource of 25,000 patients, from which subjects meeting inclusion criteria for approved downstream functional and clinical studies can be identified and recalled. Subjects would be recruited from our existing network of UK IBD Genetics Consortium (UKIBDGC) collaborating hospitals. The study coordinators will train CRN (clinical research network) nurses in each site to organise recruitment, consent, sample and data collection. Such CRN nurses are paid by the NIHR: their contribution to this study would be mandated if it is funded by the MRC. All IBD samples and data will be submitted to the NIHR BRC-MRC BioRepository team at Addenbrooke's, Cambridge. They have substantial expertise in high-throughput biological sample management, using LIMS tracking with automated storage and retrieval. Processing of all IBD samples will be undertaken by BioRepository personnel using established SOP's. DNA and serum will be extracted and quality checked using automated systems and deposited in fully monitored low temperature storage. Dr Tim Peakman, Executive Director of UK Biobank, will provide strategic guidance on biobanking issues. Once UK Biobank BioRepository South is complete the intention is to move the IBD Bioresource to this new facility. An IBD Bioresource management committee co-chaired by PI Parkes will, with the study coordinators, oversee recruitment and liaison with clinical centres. Proposals to use the IBD Bioresource will be reviewed by the NIHR BioResource scientific advisory board, including UKIBDGC representatives. Recall of patients for approved projects will be handled through the existing Cambridge NIHR BioResource mechanism. Data generated on IBD Bioresource subjects (existing genotyping and sequencing data generated from our UKIBDGC studies) will be held on the central NIHR BioResource database and accessible to collaborating researchers.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: ORAL AND GASTROINTESTINAL
Title: Autologous Macrophage Therapy for Liver Cirrhosis
Funder: Medical Research Council

Abstract: The only curative option for end-stage cirrhosis is liver transplantation but donor organ availability cannot meet demand and many patients die waiting for a suitable organ. Our work has helped to define the role of macrophages in the reversal of liver fibrosis. In rodent models of liver injury and fibrosis bone marrow derived macrophages (BMDMs) induced regression of scarring and stimulated liver regeneration. BMDM injection increased hepatic matrix metalloproteinases, increased IL-10 and reduced hepatic fibrosis. BMDM injection activated hepatic progenitor cells (HPCs), improved liver regeneration and liver function. BMDMs secreted tumour necrosis factor-like weak inducer of apoptosis (TWEAK) which induces HPC expansion and Wnt, which differentiates HPCs into hepatocytes. Our study group are patients with cirrhosis, below the listing threshold for liver transplantation (MELD score <15, UKELD <50). In this group small changes in liver function have a major impact on survival and morbidity. We will conduct a first in human study of repeated autologous CD14+ monocyte derived macrophage (MDM) therapy for liver cirrhosis with the aim of reducing liver scarring and promoting liver regeneration. We have found that cirrhotic patients can tolerate the clinical leukapheresis procedure as well as healthy controls and yield high numbers of CD14+ monocytes (typically 109 per leukapheresis). We have developed a GMP compatible protocol to differentiate CD14+ monocytes into mature monocyte derived mature macrophages (MDMs). These human MDMs have a similar gene, surface and functional profile as the regenerative mouse BMDMs. In an immunodeficient mouse model of chronic liver injury MDMs reduced inflammation and scarring and stimulated regeneration. The study will involve a cell dose escalation study, followed by a repeat cell administration study. Measured outcomes will include serum markers of liver function and fibrosis and 31P-Magnetic Resonance Spectroscopy.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL