NIHRDataInsights/HRCSData huggingface dataset:
Title: Human Tregs with 'direct' allospecificity can prevent rejection of human hepatocytes in a humanised mouse model.
Funder: Medical Research Council

Abstract: Liver transplantation (LT) is a successful treatment for end-stage liver disease. Despite this, long-term survival remains suboptimal because of the morbidity and mortality associated with long term use of immunosuppression (IS). There is, therefore, a pressing need to devise protocols that induce a sustained state of ‘specific‘ tolerance to donor liver alloantigens in order to minimise or completely withdraw IS. CD4+CD25+FOXP3+T cells (Tregs) play an important role in the induction and maintenance of immune tolerance and promote transplantation tolerance in animal models. Clinical protocols, using ‘polyclonal‘ Tregs has been shown to inhibit graft versus host disease (GvHD) after haematopoietic stem cell transplantation. Based on our prior work with mouse Tregs we hypothesise that the use of donor alloantigen-specific Tregs will confer the additional advantage that their immunomodulatory function would be concentrated at the site of the transplant with avoidance of pan-suppression. Of importance, alloantigens can be recognised by T cells either as intact HLA molecules presented by donor-derived antigen presenting cells (APCs) (‘direct‘ pathway) or after processing of allogeneic HLA molecules to produce allopeptides that can be presented by recipient HLA molecules expressed by recipient APCs (‘indirect‘ pathway). We aim to generate Tregs with ‘direct‘ allospecificity to promote the induction of ‘specific‘ tolerance characterised by prevention of rejection in a humanised mouse model of hepatocyte transplantation. We will address this in three ways: First, polyclonal Tregs will be isolated and expanded from peripheral blood of healthy volunteers. Rapamycin and all-trans retinoic acid will be used to promote the stability of these cells in vitro and to optimise the expression of CXCR3, a chemokine receptor involved in T cell migration to the liver. Second, Tregs with ‘direct‘ allospecificity will be generated by co-culturing Tregs with the best allogeneic APC (dendritic cells vs B cells); alloactivate Tregs will then be enriched by bead separation after addition of antibodies specific for activation antigens and expanded. The antigen specific suppressive function of these cells will be evaluated. Third, a humanised mouse model of hepatocyte transplantation will be used to assess the migratory ability, suppressive function and stability of antigen specific Tregs in vivo. This research program will address the current challenges facing LT, namely the shortage of donor organs and the complications of IS. It focuses on the therapeutic application of Tregs in the context of LT. The clinical translation of this work will lead to the generation of tolerance promoting protocols used to increase the pool of ‘operationally‘ tolerant LT recipients.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: What is the current burden of Irritable Bowel Syndrome in primary care and cost effectiveness of referral to secondary care?
Funder: Medical Research Council

Abstract: Irritable bowel syndrome (IBS) symptoms are present in 10-20% of the population and associated National Health Service expenditure may be as great as #100 million per year. Despite this, current and detailed data from large numbers of patients for occurrence, consequence, mortality and costs related to IBS in the UK is lacking Aims To determine the burden and consequence of a diagnosis of IBS in primary care and the cost-effectiveness of referral to secondary care Objectives 1. What is the contemporary epidemiology of IBS in UK primary care? 2. What is the epidemiology and change in health care utilization associated with secondary care referral? 3. What is the impact of secondary care referral on health related quality of life (QoL) in IBS? 4. What is the economic burden of IBS in the UK and what is the cost benefit of secondary care referral? Methodology 1. A cohort will be constructed using the General Practice Research Database (GPRD) to analyse incidence and prevalence of IBS, frequency of secondary care referrals and co-morbid conditions, prescription patterns and mortality rates 2. Using the GPRD derived cohort a self controlled case series analysis will assess any change in the number of GP consultations, prescriptions, hospital admissions, investigations and sick notes before and after referral to secondary care 3. A self-controlled questionnaire based case study of new referrals recruited from gastroenterology clinics will assess changes in QoL associated with the consultation. 4. A cost-effectiveness model will be constructed using results from the above studies based on a hypothetical cohort of IBS patients compared to the general population Scientific and medical opportunities This fellowship offers excellent training in clinical epidemiology and health economics using database and clinical research methods with medically important outcomes. The large numbers of patient data will allow better understanding of current epidemiology to inform patients, clinicians and researchers. There is currently no standardised referral pathway for patients with IBS. Assessing the impact of referral from the patient perspective and changes in health care utilisation will provide evidence to standardise practice and inform policy. An accurate and contemporary analysis of cost burden of IBS will allow optimal use of resources and this model can be used to assess other economic questions within IBS. Routinely available data reflects actual clinical practice and this study will continue to develop the methodology required to use it to create future health economic models in many disease areas.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: ORAL AND GASTROINTESTINAL
Title: Why do pancreatic beta cells waste energy?
Funder: Medical Research Council

Abstract: The physiological role of pancreatic beta cells is to secrete insulin when blood glucose levels are high. When the glucose concentration rises, beta cells increase their oxidative glucose catabolism, which causes an increased cytoplasmic ATP/ADP ratio that in turn triggers insulin release. This glucose-stimulated insulin secretion (GSIS) is only possible if glucose oxidation is coupled tightly to ATP synthesis. Surprisingly in this respect, beta cell mitochondria contain an uncoupling protein (UCP2) that uncouples these processes and thus lowers the efficiency of oxidative phosphorylation. UCP2 activity consequently wastes energy and impairs GSIS. As such, UCP2 seems detrimental to beta cell function and the important question therefore arises as to why this protein has not ended on the evolutionary scrapheap. With this research proposal I aim to clarify the evolved function of UCP2 in pancreatic beta cells by testing the hypothesis that UCP2 activity regulates the cells? physiological response to fluctuations in nutrient supply. My functional model makes clear predictions as to UCP2 levels and activity in beta cells subjected to various nutritional conditions. The model also predicts how GSIS is affected by these conditions and how UCP2 is involved in the nutritional effects. I will test these predictions directly in INS-1E insulinoma cells, a widely used beta cell model, and in primary pancreatic islets. Both these systems will be exposed to mixtures of glucose, fatty acids and amino acids that mimic nutrient starvation, abundance or excess as well as the intermediate nutrient supply that occurs between meals. UCP2 levels will be established by Western analysis, whilst UCP2 activity will be inferred from cutting-edge bioenergetic analysis, involving a Seahorse extra-cellular flux analyzer, and from reactive oxygen species measurements. UCP2-ablated systems, achieved through either RNAi or genetic knockout, will be used to confirm UCP2 activity inferences unequivocally. Perifused INS-1E cell clusters and rodent islets with and without UCP2 will be used to establish the involvement of UCP2 in the effect of nutrient supply on GSIS. Continuous measurements will reveal temporal GSIS kinetics and will distinguish between triggering and amplifying GSIS mechanisms The outcomes of the proposed research will have a positive impact on the fundamental understanding of beta cell biology. Moreover, the improved insights in the physiological role of UCP2 in beta cells will benefit a rational evaluation of the safety of UCP2 as a therapeutic target in the treatment of type 2 diabetes or in beta cell transplantation strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: Suppressor of cytokine signaling 3 is a key regulator of intestinal epithelial homeostasis.
Funder: Medical Research Council

Abstract: In a healthy human adult the single layer of intestinal epithelial cells (IEC) lining the gastro-intestinal tract replenishes itself approx. every 4-5 days. This high rate of proliferation is second only to haemopoetic cell lineages, therefore IEC represent a population of cells requiring careful regulation of cell division. Recent studies have highlighted the role of microbial-sensing Toll-like receptors (TLR) in maintaining IEC homeostasis. Under some circumstances, such as following insult to the intestine during pathogenic viral and helminth infection, hyper-proliferation of the epithelium is required to expel the invading pathogen. However, sustained excessive proliferation of IEC can lead to dysplasia and cancer. Identifying factors that govern the balance between intestinal replenishment and resistance to infection, without predisposing to dysplasia and cancer, is key to understanding how intestinal homeostasis is maintained. Evidence implicates suppressor of cytokine signalling 3 (SOCS3) as a modulator of cellular proliferation. SOCS3 acts as a negative feedback inhibitor to regulate TLR-induced inflammatory signalling pathways that promote proliferation. In 2007, the P.I. published studies showing that SOCS3 inhibited growth of colonic tumours in a model of inflammation-induced cancer. The experiments outlined in this proposal are designed to investigate the role of SOCS3 in balancing the magnitude and/or duration of ?inflammatory? signalling, controlling normal IEC homeostasis, using both in vitro and in vivo models. Understanding the mechanisms that control IEC homeostasis are key to future therapies to modulate the rate of epithelial replenishment, repair and renewal important in many diseases such as intestinal pathogen infection, inflammatory bowel disease and colon cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: Role of CXCR6/CXCL16 in steatohepatitis
Funder: Medical Research Council

Abstract: Aim: The chemokine receptor CXCR6 is expressed by specific subsets of effector lymphocytes that we have shown to be present within the inflamed liver. The present project will define the role of CXCR6 and its chemokine ligand CXCL16 in the pathogenesis of hepatitis and liver injury with the object of defining CXCR6 as a therapeutic target in liver disease. Objectives: To define i. CXCL16 expression on parenchymal and non-parenchymal cells in normal and diseased liver ii. The functional lymphocyte subsets that express CXCR6 in the inflamed liver iii. The role of CXCR6/CXCL16 in lymphocyte recruitment to and positioning within the liver iv. The effect of manipulating CXCL16/CXCR6 in murine models of liver inflammation Design and Methodology: 1) Human studies: lymphocytes, parenchymal and non-parenchymal cells will be isolated from livers removed at transplantation in our Unit allowing me to define a) expression patterns of CXCL16 and CXCR6 in normal and diseased liver using immunohistochemistry, flow cytometry and qRT-PCR b) functional lymphocyte subsets that express CXCR6 using flow cytometry and intracellular cytokine staining c) the function of CXCR6/CXCL16 in the recruitment of lymphocytes using flow-based adhesion assays incorporating human hepatic endothelium and stellate cells to model the hepatic sinusoid in vitro d) the effect of CXCR6/CXCL16 interactions on the activation, survival and cytokine secretion of interacting lymphocytes and epithelial cells. 2) Murine models of liver inflammation: models established in our laboratory will be used to determine the effect of inhibiting CXCR6 in vivo using blocking antibodies, small molecule inhibitors and genetically modified mice to define the role of CXCR6 in liver inflammation in vivo. 3) Development of therapeutic CXCR6 inhibitors: I will spend time at Chemocentryx Inc in Paolo Alto testing the potential of novel small molecule inhibitors to block CXCR6 dependent responses and then apply the inhibitors to the in vitro and in vivo models available in Birmingham. Scientific opportunities/Medical opportunities The project will provide a superb training in cellular immunology within the Centre for Liver Research and the MRC Centre for Immune Regulation. I will participate in the development of novel CXCR6 antagonists during my stay at Chemocentryx, a SME who lead the world in the development of chemokine receptor antagonists. The information I generate will potentially lead to proof of concept clinical trials in liver disease using CXCR6 inhibitors within 5 years.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: Over two and half years to study Liver Directed Gene Therapy for Patients with a Rare Inherited Disorder of Protein Metabolism: Argininosuccinic Aciduria
Funder: Action Medical Research

Abstract: Background_x000D_ Argininosuccinic aciduria (ASA) is a rare but serious inherited disease causing impaired protein breakdown by the liver. Normally, unwanted proteins are broken down in the liver to produce ammonia. Ammonia is toxic and rapidly converted to a product called urea via a process in the liver called the urea cycle. In ASA, a genetic mutation means that one of the proteins (an enzyme) essential for the urea cycle to work is missing and therefore high levels of ammonia accumulate within the body. Ammonia is especially toxic to brain cells and babies with ASA can fall into a coma and die soon after birth. In milder cases, ASA causes delayed development and learning difficulties as the child grows. Metabolic disorders of this type are known collectively as urea cycle defects and around 100 babies with these conditions (including 5 to 10 with ASA) are born every year in the UK. Current treatment of ASA is by a protein-restricted diet combined with medication. Unfortunately, these measures often fail to prevent long-term complications such as epilepsy, developmental delay and liver disease and patients may have episodes of acute liver failure. Therefore new approaches are needed to improve treatments and help children with this metabolic disorder._x000D_ The research project_x000D_ Dr Baruteau plans to investigate gene therapy of ASA in a mouse model. Viral vectors will be used to deliver a copy of the missing gene to the liver cells of mice with ASA. A viral vector is a modified and harmless version of a virus widely used in genetic research as a way of getting genes into target cells. If the gene can be successfully introduced into mouse liver cells, they may then be able to produce the missing enzyme and breakdown proteins normally. Two different viral vectors will be tested and the effects of giving treatment before and after the mice are born will be compared. This research will provide a better understanding of the use of gene therapy in this condition and be of direct benefit to patients with other urea cycle defects and to hundreds of patients with genetic disorders affecting proteins produced in the liver. Citrullinaemia type 1 (CT1) is another disease with a urea cycle defect causing similar problems to ASA. A group of researchers in Sydney, Australia are working on gene therapy of CT1 in mice. Alongside his research on ASA, Dr Baruteau plans to help set up a database of patients with ASA and CT1 in the UK and Europe. This would be of benefit to all researchers in the field of urea cycle defects and pave the way for successful research to be further tested in patients.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Stiffness and position control for soft robotic devices suitable for colo-rectal surgery
Funder: Academy of Medical Sciences

Abstract: My project aims at creating a miniaturised soft, stiffness controllable robotic manipulator based on an antagonistic actuation principle – combining tendon-driven and pneumatic air actuation. My field of clinical application will be minimally invasive surgery. In particular, procedures such as colo-rectal surgery create demand for the development of new inherently safe, surgical tools to aid surgeons in their work by offering higher manoeuvrability and on-demand stiffness. Robotics has been shown to have a role in colorectal surgery with the potential to improve patient outcomes. Currently, the da Vinci Surgical System by Intuitive Surgical dominates the market. However, despite the ‘wristed’ nature of the surgical tools that can be operated remotely via a user input console, the current robotic platform utilises rigid or ‘straight’ instruments. Thus, there remain difficulties in accessing important parts of the abdominopelvic cavity and the full potential of the robotic platform is not exploited. My proposed project is fundamentally different – the deployment of a flexible soft, stiffness-controllable surgical manipulator is proposed. Hardware elements (robot structure, material research, actuation system) and software (mathematical modelling, model-based control) of the overall system will be developed. The actuation principle of the stiffness mechanism will integrate fluidic and tendon-driven actuation into a soft, silicone-based structure. This antagonistic method combines the advantages of tendon-driven and fluidically actuated systems and goes beyond what current soft, stiffness controllable robots can achieve. Computational analysis describing the kinematics of the manipulator will be developed to control the stiffness and position of the flexible soft manipulator simultaneously.


Research activity codes: 5.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL
Title: The development of 3-dimensional implantable liver organoids
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Liver disease is the 5th most common cause of death in the UK. 16,087 people in the UK died from liver disease in 2008, a 4.5% increase since 2007 and trends are rising. Liver disease kills more people than diabetes and road deaths combined (REF: Office for National Statistics: Health Service Quarterly, Winter 2008, No. 40 p59-60). The only curative option for end-stage cirrhosis and acute liver failure is liver transplantation, however organ availability cannot meet demand and many patients die waiting for an organ. Those who undergo transplantation require lifelong immunosuppression with concomitant risks of infection, cancer, renal and cardiovascular disease. Thus, there is a clear imperative to identify alternatives to liver transplantation. Recent studies have shown human pluripotent stem cells (hPSC) co-cultured with MSCs and endothelial cells can form primitive liver organoids (Takebe et al. Nature 2013). While providing proof of concept the in vitro derived spheroids are tiny and lack a functional biliary system, requiring transformative innovation before they can be used clinically. To deliver this we have assembled a team with complementary expertise in the production and use of stem cell derived hepatocyte and cholangiocytes-like cells, hepatocyte niche construction, three-dimensional scaffold production and in vivo modelling. This collaborative group includes scientists and clinicians with experience in human cell production, GMP cell production and clinical cell therapy for liver disease. This group is ideally placed to translate these pre-clinical observations into a therapy for patients with liver failure or metabolic liver diseases, and particularly the use of liver buds derived from genetically corrected iPS cells in the case of liver disease caused by single gene defects.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Novel therapeutic approaches to malnutrition enteropathy
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The persistently high mortality of complicated severe acute malnutrition (SAM) is unacceptable for a so-called benign condition. While community management of SAM achieves historically low mortality rates in uncomplicated cases, our hospital practice confronts us daily with the reality of the most severe and complicated cases, for which current management algorithms are inadequate. One central pathophysiological derangement is malnutrition enteropathy, which is characterised by epithelial barrier breakdown and associated with very high levels of microbial translocation and systemic inflammatory responses. Children with SAM and malnutrition enteropathy often, but we suspect not always, have persistent diarrhoea. It is this group of children we propose to recruit into two consecutive parallel group randomised phase 2 trials. In the first part, eligible children will be randomised to one of four novel interventions or to standard care, and evaluated by the response primarily of non-invasive biomarkers and secondarily of simple clinical indices of response (diarrhoea volumes, appetite and play, weight gain). These interventions are bovine colostrum, N-acetyl glucosamine, teduglutide and budesonide. In the second part, the most promising intervention will be compared against exclusive elemental feeding using an amino acid-based tube feed. In the second part, endoscopic biopsies and confocal laser endomicroscopy will be used to evaluate response and confirm safety at a mucosal level. The objective of the study as a whole is to identify an agent or agents which can contribute significantly to mucosal healing. The agent(s) will then be further evaluated in a large multi-centre phase 3 trial, well powered to detect reduced mortality as a primary endpoint. We anticipate that the success of this phase 2 trial will be apparent not just in terms of therapeutic progress but in enhanced understanding of pathophysiology.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: PREdiCT - The Prognstic Effect of Environmental Factors in Crohn's and Colitis
Funder: Chief Scientist Office, Scotland

Abstract: The major aim of this study is to identify the environment and gut microbiota factors that predispose to disease flare and influence disease outbreak in IBD. A central hypothesis we wish to test is that reduced dietary fibre intake results in increased rates of disease flare by reducing microbial diversity (measured by total gene count) and luminal conentrations of key short-chain fatty acids. Further, we aim to build intelligent predictive models of disease behaviour and prognosis combining phenotypic, environmental and biological data inputs of direct clinical utility.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL