NIHRDataInsights/HRCSData huggingface dataset:
Title: CLDF/Core Grant: Investigation of myofibroblast αv integrins as an anti-fibrotic target in biliary atresia and fibrosis
Funder: CORE

Abstract: In very broad terms what is the problem that this project is going to address?Biliary atresia is a devastating condition which causes inflammation and destruction of children’s bile ducts and can lead to biliary fibrosis (scarring of the liver), liver failure and death. When biliary fibrosis becomes severe, the liver begins to fail and currently our only available treatment for end-stage liver scarring is transplantation. However a shortage of donor organs means many patients die on the waiting list, and patients undergoing liver transplantation have to take immune system suppressing drugs for the rest of their life. Therefore effective new treatments for biliary atresia and fibrosis are urgently required.Who is collaborating with you on this project, in what capacity and where are they based? What will this project do and how long it will take?Myofibroblasts are specialised cells within our liver that are the major source of scar tissue during biliary fibrosis. Therefore these cells are an attractive target to study further in our search for effective new treatments for biliary atresia and fibrosis. In order to study the molecules in myofibroblasts that might be responsible for causing scar formation during biliary atresia, we will use models that allow us to remove specific molecules within myofibroblasts to see if this reduces scar formation. Integrins are molecules which allow cells to communicate with each other and also with areas of scar within the liver. We will use models to remove a specific integrin, the alpha v integrin, from myofibroblasts to assess whether this protects from biliary fibrosis. In addition, we will use a new drug (CWHM12) that blocks alpha v integrins to assess whether this drug can protect from biliary fibrosis. We will also isolate liver myofibroblasts from patients with biliary atresia and assess whether CWHM12 can switch off scar-producing genes in these cells. This project will begin in August 2014 for 3 years, and a final report will be completed by August 2017. If we find that this new drug blocks fibrosis in models of biliary fibrosis, and is also able to block scar production in myofibroblasts isolated from human biliary atresia patients, then this will underpin the design of clinical trials to assess whether alpha v integrin inhibitors can block (or even reverse) liver scarring in patients with biliary atresia, and also other causes of biliary fibrosis. If successful, this would potentially represent a major step forward in the care of these patients as it could significantly reduce the need for liver transplantation.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Development of the Dynamic Gastric Model
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The Dynamic Gastric Model (DGM) is a physical apparatus which accurately simulates the physical and biochemical processes that occur within the human stomach. It allows samples to be taken at any stage of digestion, which would be difficult, expensive and ethically challenging in humans or animals. The DGM is based on 15 years of research including human validation studies using MRI to determine the physical behaviour of the human stomach during digestion. We now need to clearly demonstrate how well it simulates the availability of nutrients or drugs in humans, and to refine the model so that it can be more widely used, and therefore reduce the reliance on expensive animal and human studies. The model will also be further developed to enable studies that would not be permitted in humans; for instance, the impact of taking drugs with alcohol, or the development of an infant formulation. These outcomes will significantly improve the commercial and scientific potential of the DGM.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: The molecular basis of bacteria adhesion to gastrointestinal mucus
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The mammalian gastrointestinal (GI) tract is home to complex bacterial communities. Most of the bacteria establish beneficial symbiotic relationships with their host, making important contributions to metabolism and digestive efficiency. The vast numbers of bacteria in the GI tract and their proximity to host tissues raise the question of how homeostatic host-bacterial relationships are established and maintained without eliciting potentially harmful immune responses. The mucus barrier, antimicrobial proteins and IgA operate together to confine symbiotic bacteria towards the outer mucus layer and protect the epithelial surface by limiting bacterial penetration. This homeostatic interaction between mucus and gut commensals is critical to maintain gut health. Intestinal pathogens have evolved strategies for subverting and evading these barriers to access host tissues. By contrast, there is currently very limited knowledge of the mechanisms by which resident members of the intestinal microbiota interact with components of the mucus barrier. Mucus-binding proteins (MUBs) are a class of cell-surface adhesins found in Gram-positive gut symbionts, shown to mediate interaction of bacteria to mucus. Building on our extensive preliminary data on the structural and biochemical properties of MUB, the purpose of this study is to determine the molecular and cellular basis of MUB interactions with receptors of the mucus layer, mucins glycans and mucosal antibodies, and assess the potential of the impact of MUB and IgA interaction on bacteria adhesion to mucus and cell response (focusing on changes in mucin, cytokine, polymeric Ig receptor expression), providing mechanistic insights into the regulation of gut microbiota homeostasis. Understanding the molecular basis of these processes will help understand how some bacteria strains exert intestinal health protection and devise intervention strategies to reinforce gut health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: Application of a commensal gut bacterium for the controlled delivery of heterologous proteins to the lower GI tract
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Oral administration is the preferred route for delivering therapeutic proteins to the gut. To be effective, significant obstacles including minimising loss of activity during transit and controlling the dose delivered must be overcome. Our technology is designed to overcome these obstacles and uses the human commensal gut bacterium, Bacteroides ovatus (Bo) to deliver therapeutic agents in the gut in response to the dietary plant based sugar, xylan. This drug delivery platform technology will be further developed using a characterised model Bo strain producing a potent anti-inflammatory agent that can effectively treat and prevent gut inflammation. Determining optimal dosing and delivery regimens and the impact of Bo and xylan dosing on resident gut bacteria and demonstrating functionality in the large bowel will achieve this. The final output will be a robustly characterised delivery technology with pre-clinical proof of safety and functionality for the delivery of therapeutic proteins


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Uncovering the molecular strategies that allow human gut symbionts to degrade insoluble dietary and host glycans
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The human colonic microbiota gains most its energy by degrading insoluble substrates such as non-digestible plant fibre, starch particles and mucin. Fermentation of these substrates has important consequences for gut metabolism and human health, but is initiated by a few specialised 'keystone' species. This project will investigate for the first time the enzyme systems and attachment mechanisms that enable keystone species of human intestinal ruminococci to degrade insoluble resistant starches (R. bromii), cereal bran (R. champanellensis) and mucin (R. gnavus). This will require functional characterisation of carbohydrate-active systems identified by bioinformatic analysis of draft genomes as playing a key role in the degradation pathways of these insoluble substrates. These include catalytic domains and modules that may be involved in binding to carbohydrate substrates, in protein:protein interactions and in attachment to the bacterial cell surface. In particular the project will investigate the putative roles of dockerin and cohesin modules in assembling enzyme complexes, which are likely to include the first case of an 'amylosome' in any microorganism, and the first case of a 'cellulosome' in a human colonic bacterium; and determine for the first time, the complement of enzymes required for mucin degradation in Firmicutes. The project will also use anaerobic co-culture studies to investigate interactions with other dominant members of the human intestinal microbiota, specifically with hydrogen-utilizing organisms, and with 'secondary' carbohydrate-utilizing species such as Bacteroides thetaiotaomicron. The impact of co-cultures and cross-feeding will be assessed upon bacterial growth, metabolite production and gene expression. Finally, selected co-culture experiments will be translated into gnotobiotic mice in order to relate bacterial utilization of insoluble substrates under in vivo conditions to changes in enzymes and metabolites relevant to health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: Nanopatterned Human Liver BioChips for drug Hepatotoxicity Screening
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Conventional drug toxicity models use rodent hepatocytes or immortalized human cell lines, which rapidly lose polarity differentiated phenotype and are not representative of normal liver tissue. Primary human hepatocytes (PHHs) exhibit phenotypic variability and instability in culture, with intermittent supply and high costs. Hepatoxicity is a leading cause of drug attrition, suggesting current preclinical models of toxicity are not universally predictive of drug effects in humans. Therefore a sustainable and scalable human hepatic in vitro cell culture platform would help generate more physiologically-relevant preclinical data for drug hepatoxicity screening. Commercially available bioengineered liver models are based on heterologous hepatic co-cultures, which may be contraindicated for pre-clinical hepatotoxicity testing. We will utilize the human HepaRG bipotential hepatic progenitor cell line as a functional surrogate to PHHs and a unique co-culture system for high-throughput screening (HTS) of hepatotoxicity. The significance of the proposed work is to develop and validate a prototype HTS-compatible HepaRG-based BioChip by directed nanopattern-guided differentiation. HepaRGs undergo a complete differentiation program, which we will exploit to assess effects of nanopattern-guided differentiation/ cellular reorganization. Thus our research will grant access to general mechanistics of external cues for the improved culture of other hepatic cell types. We will determine the interplay between nanoengineered substrates and hepatic phenotypic function by assessing: *Nanotopographical control of HepaRG differentiation on fabricated nanopatterned polymer slides *Define optimal configuration most predictive of in vivo-like metabolism *Perform rigorous hepatotoxicity testing interrogated with automated HTS-compatible CellProfiler *Using the above criteria, integrate the system for HTS using a novel ubiquitous 'BioChip' HTS platform for hepatotoxicity testing


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: A physiologically relevant in vitro model gut system
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Project Objective 1 Market Research/Assessment and competitor analysis Expert consultancy will be sought to conduct a detailed assessment into the three major markets which have been identified for the model gut system: - Nutraceutical & Pharmaceutical Companies including natural health products - Food and Drink/Ingredients Companies - Academic researchers This market research will determine potential customers for the model gut system in each of these market sectors and characterise the customers' needs, priorities and areas of current development, research and innovation. This assessment will also aim to provide insight in to R&D budgets, key decision makers and opinion leaders and what motivates buying decisions in each of these major market sectors. The market research will also include an assessment of potential barriers and opportunities for improvement to the product/ service and diversification. A key aspect of this commissioned report will be to look at the processes by which these sectors conduct their research and product development and what barriers there are to the outsourcing of these activities. It will also aim to establish how organisations meet the requirements of regulatory bodies such as EFSA (European Food Safety Authority). This market research will also include an assessment of competitors in the field, including other organisations offering in vitro models, but also companies competing with different methods and also in-house research departments. The research will also aim to establish the costs and charges of competitor models. Project Objective 2 Sector Specific Networking Market specific networking and marketing/promotion of the service will be conducted. By attending sector specific trade shows and conferences which will allow us to identify and directly engage with a range of would be customers, partners, and key industry players. Peter Chater attended Fi Europe 2013 and generated interest in the Model Gut system and we would like for one or more of the team to attend the Vitafoods Europe conference between the 6th and 8th of May 2014 to follow up on this interest. The networking will also target major academic, nutraceutical and food and drink, and ingredients conferences.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: ORAL AND GASTROINTESTINAL
Title: To quantify the effect of broccoli consumption on the diversity and metabolism of the gut microbiota, with focus on sulphate reducing bacteria
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The human gut microbiota is extremely complex with more than 1000 different bacterial species composition and metabolic activity of which has significant impact on the host health. Consumption of cruciferous vegetables has been correlated with numerous health benefits. The bioavailability of the chemicals present in such foods and the nature of the impact on the host is dependent on their absorption but also their biotransformation by gut microbiota to products which may be more bioactive. In addition, the metabolism of many of the dietary components that reach the colon will impact on the composition and activities of the gut microbiota. In this project we aim to focus on consumption of broccoli that is rich in sulphates and sulphur containing bioactives particularly the glucosinolates. The key questions we will address are (a) What is the impact of broccoli consumption on the composition and metabolic activity of gut microbiota? The faecal samples collected during human intervention studies will be assessed using culture independent microbial profiling methods (FISH, QPCR, pyrosequencing) and metabolomics using proton NMR to obtain a comprehensive information on modulation and metabolic activity of total gut bacteria and (b) What is the response of gut microbiota to sulphates and defined sulphur containing dietary components? In vitro colon model systems that replicate the microbial and physiological condition of the large intestine will be utilised to assess the biotransformation of sulphur compounds. We will measure the effect of such chemicals on the diversity and metabolic activity of sulphate reducing bacteria (SRB) which are an important component of the gut microbiota associated with production of toxigenic hydrogen sulphides that adversely affect the gut health.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigating the impact of dietary interventions for irritable bowel syndrome on luminal microbiota, symptoms, nutrient intake and quality of life
Funder: Department of Health (England)

Abstract: Irritable bowel syndrome (IBS) causes abdominal pain and change in bowel habit. The low FODMAP diet might improve these symptoms but it lowers the numbers of bifidobacteria (a type of bacteria) in the bowel. Probiotics are friendly bacteria that increase bifidobacteria. This study aims to investigate if a low FODMAP diet and probiotics affect the gut bacteria, IBS symptoms, diet and quality of life. It is expected bifidobacteria will be maintained and IBS symptoms will improve. This study will help understanding the effects of this diet on the bowel and may impact on guidelines for how IBS is managed.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.8 COMPLEMENTARY
Health categories: ORAL AND GASTROINTESTINAL
Title: Understanding the Systems, Organisational and Patient Barriers and Facilitators to Quality Improvement in Primary Dental Care: Prevention and Management of Dental Caries in General Practice
Funder: Chief Scientist Office (Scotland)

Abstract: Aim To inform the development of theoretical, evidence-based, practical and effective interventions for the translation of national clinical guidance recommendations for the prevention and management of dental caries into practice. Research questions The key research question is:  what are the systems, organisational, and patient factors that influence the delivery of optimal care in the prevention and management of dental caries in primary dental care? The specific objectives are: 1. to identify the barriers and facilitators at the systems, organisational, Prof.essional and patient levels to the delivery of optimal prevention and management of dental caries in primary dental care; 2. integration of mixed methods to characterise management of caries; 3. to identify potential interventions for evaluation in a future study.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: ORAL AND GASTROINTESTINAL
Title: Supportative Care in the Community for People Living with Advanced Liver Disease: a feasibility study
Funder: Chief Scientist Office (Scotland)

Abstract: Liver disease is the fifth largest cause of death in the UK and affects younger people. Palliative care is poorly developed. We will trial a supportive care liver nurse specialist intervention to improve care coordination and quality of life for patients and carers living with advanced liver disease. Patients with advanced, progressive liver disease will be identified in the gastroenterology unit at the Royal Infirmary of Edinburgh. Participants (n=60) will be randomised 2:1 to intervention or usual care. The intervention group will receive support, care coordination and anticipatory care planning from the study nurse specialist. Resource use (particularly hospital bed days), care planning processes and quality of life outcomes will be analysed. We will interview patients, carers and healthcare professionals to explore acceptability, effectiveness, feasibility and potential improvements in this innovative intervention. The pilot will clarify recruitment processes and candidate primary and secondary outcomes measures for a future multi-site RCT.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: ORAL AND GASTROINTESTINAL
Title: Scottish Alcoholic Liver disease Evaluation of epidemiology and costs of first and subsequent hospital admissions (SCALE)
Funder: Chief Scientist Office (Scotland)

Abstract: Alcoholic liver disease (ALD) is a significant burden on health. Alcohol consumption accounted for 3.8% of global mortality in 2004 and ALD is an important contributor to the total burden of alcohol related harm. Despite the considerable amount of research into the epidemiology of alcohol related harm in Scotland, the epidemiology of first ALD hospitalisations is unknown, yet it is such work that will provide a better indication of future burden of disease in Scotland. Using this cohort of patients, trends over time, readmissions, mortality and economic burden will be analysed taking into account different subgroups (sex, age, socio-economic deprivation, geographical regions, comorbidities). The epidemiological research will feed into the development of an ALD health economic model. This will be invaluable in planning future resources and allowing sensitivity analyses/scenario planning to assess the health impact of prevention strategies and their cost-effectiveness.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining the intestinal microbiota in premature neonates.
Funder: Department of Health (England)

Abstract: Highly premature infants are susceptible to NEC, a poorly-understood life-threatening bowel disorder. Bacteria proliferating abnormally in the bowel are believed to play an important part in its cause. Daily faecal samples will be collected from premature infants in the intensive care unit from birth until discharge. By using new molecular detection techniques we aim to define all the different types of bacteria present in the faeces. By comparing the bacteria in the faeces of babies who go on to develop NEC with those of well babies, differences characteristic of the condition will be identified, aiding design of preventative or treatment strategies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: ORAL AND GASTROINTESTINAL
Title: Development of a child-centred caries specific measure of oral health related quality of life
Funder: Department of Health (England)

Abstract: Dental decay (caries) is the most common disease of childhood, affecting 30% of British 5-year-olds. It may cause considerable problems for those affected, despite it being almost entirely preventable. Currently, there is no measure to evaluate the impact of this disease or its treatment. Such a measure would be required to assess patient-reported outcomes in clinical trials. This project will explore the impact of caries and its related treatment in children aged 5-16 years, and will develop a child-centred questionnaire to measure this. The use of this questionnaire will help to improve dental services for children.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: ORAL AND GASTROINTESTINAL
Title: Understanding and improving the quality of end-of-life care for patients with end-stage liver disease; a longitudinal study of symptoms and experience.
Funder: Department of Health (England)

Abstract: End-stage liver disease (ESLD) is the fifth most common cause of death. This study aims to understand the needs of people with ESLD over time and how they are addressed. Using questionnaires we will ask patients about their symptoms, how bad they are and what help they need. We will talk to a smaller number of patients and carers about their experiences in depth. We suspect that ESLD patients have severe symptoms that are not currently being treated well, with worse end-of-life care and increased NHS costs. Our results will highlight ways to improve care for ESLD.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: ORAL AND GASTROINTESTINAL