NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of host-derived sialic acid in the biology of periodontal pathogens
Funder: The Dunhill Medical Trust

Abstract: Periodontitis is an inflammatory disease leading to tooth loss and affects over 300 million people worldwide, particularly the elderly. Aggressive forms of disease affect approximately 10% of the UK population and are associated with a small group of bacterial pathogens including the understudied Tannerella forsythia. The ability of these bacteria to form biofilms on the surface of the tooth structures and to interact with oral epithelial cells is key to pathogenesis. Our recent work has idenitified that sialic acid-containing host molecules stimulate Tannerella forsythia growth, suggesting it is a key molecule for periodontal pathogen biofilm formation and host-interaction. This provides the potential for novel approaches to treatment. We will focus on investigating the role of sialic acid in inter-bacterial and bacteria-host cell interactions of Tannerella forsythia by using inhibitors of sialidase enzymes and mutants deficient in sialic acid scavenging. This work will enhance understanding of this important disease of ageing.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: ORAL AND GASTROINTESTINAL
Title: Improving therapy for ulcerative colitis patients with active disease: the impact of 5-aminosalicylic acid induced expression of Dual Oxidase 2 on risk of UC associated colorectal cancer
Funder: The Dunhill Medical Trust

Abstract: Colonic DUOX2 expression produces hydrogen peroxide, a reactive oxygen species (ROS), and is up-regulated in active ulcerative colitis. Overproduction of hydrogen peroxide amplifies ROS-induced genetic damage and causes cellular transformation which may explain the increased cancer risk associated with chronic ulcerative colitis (UC). Mesalazine (5-ASA) is an effective induction and maintenance therapy for UC. 5-ASA has been shown to be chemo-preventative for UC associated cancer and scavenges ROS. Recently, we found that 5-ASA reduces DUOX expression in quiescent colitis. However in active disease 5-ASA reduces pro-inflammatory cytokine production but directly stimulates DUOX2 expression. Therefore although 5-ASA is therapeutic during active disease it may increase risk of UC associated cancer. It is unclear whether DUOX2 up regulation is caused directly by the 5-ASA formulation being taken or forms part of a feedback loop generated by 5-ASA’s scavenging properties. Our results indicate a need for additional DUOX2 suppression measures during UC-associated flares.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: non-invasive assessment of haemdynamic response to beta-blockers using magnetic resonance imaging in patients with portal hypertension
Funder: Chief Scientist Office (Scotland)

Abstract: Portal hypertension underlies most of the fatal complications of cirrhosis. Current treatment with non-selective beta-blockers (e.g. propranolol) can reduce the risk from variceal bleeding, but less than one third of patients respond to these drugs and at least a fifth stop treatment due to side effects. New drugs are emerging that may be more effective and better tolerated. We need to understand why some patients do not respond to beta-blockers (so alternative approaches can be sought) and to monitor response we need to develop an appropriate diagnostic test; one that is widely available and acceptable to patients. We have optimized a magnetic resonance-based method to study the circulation in patients with liver disease and wish to determine its value in studying the effects of drugs in order to target treatments more effectively (‘personalized medicine’). In this pilot study, we will examine an established drug (propranolol) and an emerging alternative (carvedilol).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: The role of NF-kB and cell shedding in Inflammatory Bowel Disease
Funder: Wellcome Trust

Abstract: We have shown that when intestinal epithelial cells are shed from the intestine they leave a gap in the epithelium which is sealed by an impermeable extracellular substance thereby maintaining local barrier function. TNF increases the rate of cell shedding and causes sealing of epithelial gaps to fail. Also we have shown that mice lacking NEMO in intestinal epithelial cells thereby preventing NF-kappaB signalling develop intestinal inflammation because of increased bacterial translocation. T hese data suggest the hypothesis that cell shedding and epithelial barrier function at gaps is regulated by TNF and NF-kappaB pathways. Epithelial gaps are best studied in vivo. We have access to all the transgenic strains and have established and published all confocal microscopic protocols required for this project. We shall determine which TNF receptor participates in regulation of cell shedding and investigate whether Suppressor of Ras-1 and Raf1, molecules we have shown to be in survival pathways, prevent cell shedding and preserve barrier function. The role of NEMO, classical and alternative NF-kappaB pathways in the preservation of barrier function and cell shedding will be investigated. These studies will bring new insights into the pathogenesis of Inflammatory Bowel Disease and suggest new targets for therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Studies into the molecular causes of Crohn's disease.
Funder: Wellcome Trust

Abstract: Crohn s disease (CD) and ulcerative colitis (UC) are called inflammatory bowel disease. Many causes have been proposed for these diseases, but none have stood the test of time. Recently we have shown major abnormalities in the inflammatory response to bacteria in these conditions. Whereas that in CD is markedly reduced, UC is characterised by prolonged inflammation. Macrophages, the conductors of the orchestra of inflammatory mediators released at sites of inflammation, are grossly abnormal in t hese two conditions. We plan to investigate the precise mechanisms that fail in CD and UC. In CD it appears to involve the cellular machinery that normally packages the inflammatory mediators the CD cells seem to move the mediators to the disposal machinery rather than to the exterior. In UC the problem appears to involve a signaling system that switches on the production and release of mediators. Acute inflammation is normally only switched on for about 24 hours, after which it suppressed. This suppression does not occur, or is delayed, in UC. We will investigate the signaling pathways normally activated in macrophages by bacteria and then determine where they are defective in UC cells. These approaches should facilitate the development of rational treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Vascular adhesion protein-1: a multi-functional enzyme involved in inflammatory liver disease.
Funder: Wellcome Trust

Abstract: The UK is experiencing a dramatic increase in liver disease and new treatments are urgently needed. Liver failure occurs when white blood cells enter the liver in response to infection or injury (hepatitis) but instead of resolving the damage they drive the formation of scar tissue (cirrhosis) by cells called fibroblasts. We will use a combination of test-tube experiments with human cells and studies in mice to determine how an enzyme called VAP-1 contributes to liver injury. Based on exciting preliminary data we shall investigate how VAP-1 recruits white blood cells to the liver and directly affects the formation of scar tissue by fibroblasts thereby promoting the development of cirrhosis. Because VAP-1 is an enzyme we will study the effects of specific enzyme-inhibitors on these processes both in the test tube using human cells and in models of liver disease in mice. The ability to manipulate the function of VAP-1 through its enzyme activity is particularly important because it p rovides a new approach for developing drugs to treat liver disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining the impact of inflammatory bowel disease associated SNPs on the immunobiology of human mucosal T lymphocytes
Funder: Wellcome Trust

Abstract: AIM: The phenotypic analysis of intestinal T lymphocytes including functional studies of genetic polymorphisms associated with Crohn's disease. Lymphocytes will be extracted from blood and intestinal biopsies from healthy individuals stratified for two key SNPs identified from GWA studies as associated with IBD susceptibility. One SNP is a coding variant in the IL23 receptor, involved in differentiation of T lymphocytes to IL17 production, and one a non-coding variant associated with chemokine receptor gene CCR6, involved in T lymphocyte chemotaxis and expressed by IL17 producing cells. Lymphocytes will be characterised and sorted by polychromatic flow cytometry based upon expression of coreceptors defining T lymphocyte sub-populations, including unconventional populations that we suggest play a key immunoregulatory role, and simultaneously analysed for chemokine receptor expression. Functional studies will examine CCR6 driven chemotaxis and IL17 differentiation in sorted mucosal and systemic T lymphocytes. cDNA from sorted lymphocyte subpopulations will be analysed for chemokine receptor and cytokine expression by qPCR and allele specific expression. Key goals include the definition of chemokine receptor and cytokine expression by populations of unconventional mucosal lymphocytes, and assessing the phenotypic and functional impact of the two Crohn's-associated SNPs on mucosal lymphocytes including the homing and cytokine production of unconventional subpopulations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Magnetic Resonance Imaging Haemodynamic Modelling in Chronic Liver Disease: development, validation and translation.
Funder: Wellcome Trust

Abstract: Liver disease is the fifth most common cause of death in the UK and the incidence is increasing. It is known that patients have major alterations in liver blood flow and although important, they remain poorly understood. For example, in some patients therapies used to prevent complications such as bleeding may do more harm than good by reducing liver blood flow, and yet we are unable to predict who will benefit and who will be harmed. Current methods of measuring liver blood flow are either hig hly invasive or unreliable. There is a need to develop a safe, non-invasive, accurate technique to measure liver blood flow. Preliminary data from the Department of Academic Radiology and Institute of Hepatology at UCL shows that liver blood flow can be non-invasively estimated in a rat model using Magnetic Resonance Imaging - a widely available and safe scanning technique. This research will develop the technique further and test how well it works in a rat model of liver disease. We will then a pply the technique to patients and confirm it works in humans. Finally we will explore how useful the test is in helping doctors monitor the effects of medication in patients with liver disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Targeting Ca2+ signals in intact native smooth muscle cells
Funder: Wellcome Trust

Abstract: Smooth muscle lines the gastrointestinal tract and blood vessels. Its contraction regulates intestinal motility and digestion and blood flow and pressure. Calcium is a major regulator of smooth muscle and controls every aspect of its activity including division, contraction and death. Calcium is important also in gastrointestinal motility disorders (e.g. of the stomach and bowel) and vascular disorders (e.g. hypertension) and drugs that modify calcium alter the function of the gastrointestinal and vascular systems to improve performance in disease. An appreciation of smooth muscle function in health and disease requires an understanding of calcium control. Calcium regulates so many different functions by doing different things in different parts of the cell. Our work seeks to understand how calcium is controlled in different parts of the smooth muscle cell. Because several separate elements of the cell interact we need to understand how calcium signals begin, how it grows and the interactions that contain the signal after it starts. This work will develop novel molecular probes and apply them with new methods to measurecalcium changes in small specific regions of the cell to understand how calcium controls every aspect of smooth muscle and so gastrointestinal motility and blood flow and pressure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: The role of CCL20/ CCR6 mediated T cell homing in hepatic ischaemia reperfusion injury.
Funder: Wellcome Trust

Abstract: The rate of liver failure is rising rapidly in the UK. Transplantation is the only available treatment for endstage liver failure, transforming the lives of recipients with an average of 22 years of additional life, but is rationed by a shortage of donor organs. Liver Transplantation requires a liver to be taken from a deceased donor, transported on ice, and reimplanted in a recipient. During this time, the blood supply to the organ is interrupted, depriving liver cells of oxygen, an injury term ed ischemia. When the blood supply is reconnected in the recipient, a further injury occurs, termed reperfusion injury. Ischemia reperfusion injury (IRI) can cause the transplanted organ to fail, often resulting in death. If the risk from IRI is judged as excessive, the organ must be discarded, compounding the donor crisis. We hope to learn how T cells of the immune system contribute to IRI. We have identified a pair of molecules (called CCL20 and CCR6) which may be responsible for bringing T ce lls into the organ after ischemia, and a novel drug which may reduce their activity. Should this drug reduce injury after ischemia, it may extend lifesaving transplantation to more patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: The therapeutic potential of chemokine and integrin manipulation in the treatment of inflammatory bowel disease.
Funder: Wellcome Trust

Abstract: The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, describe a heterogeneous spectrum of disorders with a diverse clinical course. Current clinical management is limited by the relatively small number of therapeutic approaches that have proven efficacious in the diseases. There is a pressing need to more fully understand the pathogenesis of IBD, the variation in phenotype between patients, and to understand the basis for individual variation in response to treatment. This project will explore the biology of chemokine receptor and integrin function in IBD-relevant systems: Aim 1: Two potential therapeutic agents (chemokine receptor CCR9 and integrin subunit B7 blocking agents) will be examined for their capacity to limit lymphocyte adhesion and migration in homeostatic and inflammatory conditions. Aim 2: To define the importance of CCR9 and B7 during active intestinal inflammation, the expression of the relevant ligands in patient tissue will be determined along with a range of appropriate biomarkers. Experiments will be performed to derive patient lymphocytes from ex vivo tissue that will be employed in the assays defined by aim 1. Aim 3: An in vivo, humanised, model of IBD will be developed. This will allow in vivo modelling of the efficacy of the above candidate drugs, and serve as a platform for future translational research in IBD.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Resident and Inflammatory Macrophages in the Intestine.
Funder: Wellcome Trust

Abstract: The large intestine contains trillions of bacteria which are essential for health. As many of these bacteria are closely related to microbes which can cause serious infections, the body has to ensure they cannot invade via the intestine. This task is carried out partly by a large population of white blood cells known as macrophages. However macrophages can cause inflammation in diseases of the intestine like Crohn s disease and also need to become very active in reaction to harmful microbes. Mac rophages in the normal colon do not make inflammatory responses to bacterial products. However during experimental inflammation, virtually all colonic macrophages respond fully, either because new cells arrive, or because the original population changes. In this project, we will use methods we have refined recently to understand how these two populations of colonic macrophages are related to each other, what their functions are, how they get there and what stops them responding in healthy intest ine. We will do this in three separate models of inflammation and infection. Overall we will find how macrophages help contribute to health and aim to help develop new treatments of inflammatory bowel disease based on targetting of inflammatory macrophages.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: The role of mesothelial cells and the p75NTR/sortilin axis in hepatic injury, fibrosis and regeneration
Funder: Wellcome Trust

Abstract: Cirrhosis develops after accumulation of scar tissue - the wound healing response of liver to injury. Hepatic myofibroblasts (hMFBs) are cells responsible for this scarring; some are present within normal liver whilst others are recruited after injury; evidence suggests that cells derived from the external surface of the liver (Wt1 expressing) may contribute. These cells may also influence development and maintanence of liver cell (hepatocyte) mass. Pre-cirrhotic fibrosis is reversible once in jury has abated. Liver enzymes degrade the scarring in parallel with hMFB loss by cell suicide (apoptosis). hMFBs express receptors for nerve growth factor (p75NTR). Addition of NGF causes hMFB apoptosis, and loss of p75NTR expression slows recovery of fibrosis. The precursor form of NGF protects hMFBs from apoptosis, an effect that may be mediated by another receptor, sortilin. I wish to: examine the contribution of Wt1 expressing cells to scarring and hMFB numbers, and to the hepatocyte mass in development and regeneration in injury; and examine the hypothesis that proNGF, via sortilin, mediates hMFB survival and slows resolution.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: The function of NOD2 in immunity to intracellular bacteria.
Funder: Wellcome Trust

Abstract: Crohn's disease is an incurable chronic inflammatory condition of the gut that leads to recurrent episodes of abdominal pain, diarrhoea and weight loss. This disease results from a failure of the immune system to tolerate the microorganisms present within the bowel and the ensuing overactivity of the immune system in the bowel wall leads to inflammation in this area. Around 50% of the risk of developing Crohn's is genetic and recently there has been great success in defining which gene variation s predispose to this disease. This proposal investigates the function of the strongest associated gene described so far, NOD2. NOD2 is an immune receptor that recognizes gut bacteria and signals to immune cells to stay silent or mount an immune response. Gene variants in NOD2 associated with Crohn's are unable to recognize bacteria normally and there is evidence to suggest this may lead to impairment of immune processing of these bacteria which may act as a trigger for inflammation. My work will address how NOD2 functions in immune cells normally in terms of commensal bacterial handling and how this function is impaired in the presence of NOD2 variants associated with Crohn's.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Scottish Consortium Translational Medicine and Therapeutics Programme: 'Relaxin as a therapeutic haemodynamic modulator in liver disease'.
Funder: Wellcome Trust

Abstract: Hepatorenal syndrome (HRS) is one of the most feared complications of end-stage liver disease. It is best described as a functional renal failure, resulting from marked circulatory dysfunction seen in the advanced stages of cirrhosis. The hallmark of this syndrome is severe renal vasoconstriction. Historically, liver transplantation was the only effective treatment for HRS but, more recently the pathophysiology underlying this condition has been defined, paving the way for newer treatment modalities. However, current pharmacological treatment of HRS is very limited and mortality rates remain extremely high. We have identified a novel approach using the peptide hormone relaxin, which has potent vasodilatory effects in a range of tissues (including the kidney). Intriguingly, relaxin has been shown to increase renal blood flow in experimental models and in healthy humans. We hypothesize that relaxin can induce renal artery vasodilation in the context of HRS, thereby increasing renal blood flow and improving renal function. I will test this hypothesis by studying relaxin receptor expression and signaling in the kidney/ vasculature, deploying relaxin in vivo in models of HRS and in a small cohort of humans with cirrhosis. I will also evaluate the utility of non-invasive MRI-based imaging in monitoring changes in visceral blood flow.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Regulation of intestinal dendritic cell function by SIRP?.
Funder: Wellcome Trust

Abstract: This project will explore how signal regulatory protein ? (SIRP?) regulates dendritic cell function in the intestine. Previous work has identified SIRP?+and SIRP?- subsets of dendritic cells (DC) in mouse and human intestine, and has suggested that these DC may play distinct roles in driving effector immuneresponses or tolerance. Mice with a non-signalling mutant form of SIRP have reduced numbers of CD103+CD11b+ DC in the intestine, as well as fewer IL-17 producing CD4+ T-cells, a population which plays important roles in controlling the intestinal microbiota and in inflammatory bowel diseases. Here we will characterise fully the functions and localisation of SIRP + and SIRP - subsets of intestinal DC, will identify the cells expressing CD47, the ligand for SIRP + and will determine how SIRP might influence other myeloid cells in different parts of the intestine. Using SIRP mutant DC and by ligating SIRP in vitro, we will examine directly how SIRP? modifies DC activation and will explore the signalling pathways involved. By comparing these parameters in steady state and after administration of adjuvants with


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL