NIHRDataInsights/HRCSData huggingface dataset:
Title: Engineering intestinal mucosal tissue grafts as a novel treatment for inflammatory bowel disease.
Funder: Medical Research Council

Abstract: Inflammatory bowel disease (IBD) affects up to 600,000 in the UK. It is a relapsing condition and repeated episodes of inflammatory damage culminate in intestinal fibrosis and increased risk of cancer. Effective treatment which promotes healing may alleviate symptoms and prevent long-term sequelae. Published data show that altering cellular micro environment can accelerate the healing process. Predicated on this principle, the aim of this project is to (i) drive induced pluripotent stem cells (IPSCs) towards intestinal epithelium cultured on a suitable synthetic biomaterial and (ii) use this as an intestinal graft to treat inflammation. This will build on our previously developed methodology for driving human IPSCs to differentiation as colon / hindgut lineages. To address this aim, I will: 1. Optimise protocols for growth of intestinalised IPSCs. I will assess the contributions of signalling pathways (eg. beta-catenin, FGF-4, EGF, BMP-4) to growth and phenotype of intestinalised IPSCs when cultured on electrospun gelatin scaffolds. I will investigate phenotype in-vitro through protein and RNA profiling and in vivo through growth characteristics following injection into the renal subcapsule of NOD SCID gamma mice. 2. Investigate the potential of novel 3D-printed scaffolds for growth of intestinalised IPSCs. These will be compared with the electropsun scaffolds. The phenotype will be assessed in-vitro and in-vivo as above. 3. Scale up the in-vitro cultures to produce synthetic tissue grafts. The growth and differentiation characteristics of these will be tested by implanting into the colon of NOD SCID gamma mice. This project will allow us to re-create intestinal mucosal tissue in laboratory conditions. This will potentially give us the means to make IPSCs a useful regenerative medicine therapy for people with IBD and provide better in vitro models of intestine.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Inhibition of T-bet-mediated transcriptional elongation as a novel therapeutic target for inflammatory bowel disease.
Funder: Medical Research Council

Abstract: Inflammatory bowel disease (IBD) affects 240,000 people in the UK, costing the NHS £720m per annum. Despite the advent of biological therapies, 30% of patients fail to respond and develop complications including bowel perforation, colorectal cancer and intestinal failure. The T-box transcription factor T-bet is essential for maintaining immune homeostasis and is implicated in the pathogenesis of IBD. T-bet is upregulated in the colonic mucosa of Crohn's disease patients, driving Th1 cell activation and inflammation. Our recent work has identified a strong association between IBD and genetic polymorphisms that give rise to abnormal T-bet binding. We hypothesise that inhibiting T-bet mediated transcriptional elongation will abrogate intestinal inflammation in preclinical models of IBD and in in vitro human IBD. We will use cyclin-dependent kinase 9 (CDK9) inhibitors (Flavopiridol, AT7591, and LDC000067) that disrupt T-bet binding to enhancer elements of Th1 gene targets. We aim to investigate the effects of inhibiting T-bet function in innate (anti-CD40 Rag-/-) and adaptive (naïve T-cell transfer) pre-clinical models of colitis. In vitro assessment will be performed by culturing colonic explants with CDK9 inhibitors for 24 hours. Pro-inflammatory cytokines and canonical T-bet target genes will then be measured using ELISA. The experiment will be repeated in vivo, delivering the compounds via intraperitoneal injection. Response will be measured by assessing clinical parameters and colonic histology. In parallel, we will study the therapeutic potential of CDK9 inhibition on lamina propria mononuclear cells (LPMCs) of IBD patients. We will isolate LPMCs from colonic biopsies and stimulate these in the presence of CDK9 inhibitors. Cytokine production will be measured by flow cytometry to determine response to treatment. Ultimately, we hope to identify a novel treatment strategy for IBD, paving the way for effective targeted therapies which will benefit patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Spectroscopic capsule technology for the detection of gastrointestinal bleeding
Funder: Medical Research Scotland

Abstract: Since the early 2000s, capsule endoscopy has revolutionised the diagnostics of the gastro-intestinal tract. Such technology is critically complex, and is developed through international collaboration. Europe sits at the forefront of the technology, developing capsules with features such as locomotion, advanced imaging and micromanipulation. In recent years, European collaboration has yielded a capsule sensor for acute bleeding that is swallowed by the patient, attaches to the stomach wall, and detects bleeding through optical measurement. Yet, such technology is limited to the stomach, missing important bleeding in other segments of the gastro-intestinal tract. The present project aims to develop a capsule sensor that can detect bleeding anywhere in the gastro-intestinal tract. In order to do so, it will use optical spectroscopy. The project addresses therefore the design of a swallowable optical spectrometer, of the data link to transmit the data outside the patient, of the power source, and of the electronics outside the patient. Finally, it will assemble the components in a complete sensing capsule and give a demonstration of its function. The project establishes Scotland at the forefront of this highly novel technology, through collaboration with Ovesco Endoscopy AG, a key player in cutting-edge developments in endoscopic capsules.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Prophylactic removal of impacted third molars (review of TA1) [ID898]
Funder: Department of Health and Social Care

Abstract: The remit of this review is to appraise the clinical and cost effectiveness of the prophylactic removal of impacted mandibular third molars. The objective is to partially update the first Technology Appraisal carried out by the National Institute for Health and Care Excellence (NICE): Guidance on the Extraction of Wisdom Teeth (TA1).1

Lay abstract: Wisdom teeth (third molars) are located at the very back of the mouth on both the upper and lower jaws, and four molars usually appear in the mouth between the ages of 18-24 years. About 15-20% of people never develop at least one of these four molars. Wisdom teeth often grow through the gums (erupt) without problems; however, sometimes, the wisdom tooth is unable to erupt properly and becomes “impacted”. When wisdom teeth become impacted there is an increased risk of decay and disease. Wisdom teeth can be surgically removed if they are diseased, or if they are likely to become diseased in the future. There are risks involved when surgically removing wisdom teeth. Risks include infection, delayed healing, and nerve damage. Current NHS guidelines recommend that impacted wisdom teeth should only be removed if there is evidence of disease or if there are repeated episodes of infection associated with the tooth. The guidance states that healthy wisdom teeth should not be removed as a preventive measure against future disease and that people with disease-free impacted wisdom teeth should visit their dentist for regular check-ups. The aim of this review is to assess the clinical and cost effectiveness of the prophylactic removal of impacted mandibular wisdom teeth compared with standard care without prophylactic removal of wisdom teeth. The evidence for clinical effectiveness will be derived from a systematic review of published randomised controlled trials, clinical studies and literature reviews. The key outcomes will be pathology (disease) associated with retention of wisdom teeth, complications following surgical removal, adverse effects of surgical treatment, and health related quality of life. The evidence for cost effectiveness will be derived from a systematic review of published economic evaluations and costing studies.

Research activity codes: 6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL
Title: Mechanical interdental cleaning for preventing and controlling periodontal diseases and dental caries
Funder: Department of Health and Social Care

Abstract: A quarter of children in the UK have tooth decay1. 83% of adults have unhealthy gums2. Caries and periodontal disease affect oral health (potentially leading to tooth loss), general health, and quality of life3, yet these conditions can be prevented by removing their cause - plaque. Mechanical interdental cleaning devices (e.g. floss) are widely recommended4 and marketed5 as an important step in self-administered plaque removal; however, recent articles in the academic and popular press6-11 have debated whether scientific evidence supports this received wisdom, some arguing that the flossing recommendation was removed from US Department of Health dietary guidelines12 because of lack of evidence of effectiveness. A Cochrane prioritisation process identified the need for this review, which will update two highly accessed and cited Cochrane reviews on flossing and interdental brushing13, and expand their scope to include children and all types of interdental cleaning device. The new contract for NHS primary care dentistry is being developed, with a focus on preventive care14, and our analysis of around 40 studies (including cross-over and split-mouth studies) will provide the clarity that commissioners, dentists and the public need in order to decide which, if any, mechanical interdental cleaning device(s) to recommend or purchase.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL
Title: Predictors of poor oral health trajectories in middle age. Who is at greatest risk?
Funder: Department of Health and Social Care

Abstract: Retaining natural teeth for life is now possible for many, but not guaranteed for all. Why not? This research will use a national dental survey to identify and understand changing patterns of oral health in the UK. These findings will subsequently inform research using a unique cohort of 1000 middle-aged individuals, followed since their birth in 1947. Using mixed methods, what they tell us now will be combined with 60 years of data to identify the determinants of their oral health as they age, with a view to shifting policy and practice towards earlier identification and intervention for future generations.

Lay abstract: Retaining natural teeth for life is now possible for many, but not guaranteed for all. Why not? This research will use a national dental survey to identify and understand changing patterns of oral health in the UK. These findings will subsequently inform research using a unique cohort of 1000 middle-aged individuals, followed since their birth in 1947. Using mixed methods, what they tell us now will be combined with 60 years of data to identify the determinants of their oral health as they age, with a view to shifting policy and practice towards earlier identification and intervention for future generations.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Gastrointestinal (GI) and Liver disorders
Funder: Department of Health and Social Care

Abstract: Aims: Short term: 1. RA1.2: Formulate C. difficile intervention strategies based on spores, toxins, phage and microbiome. 2. RA2.1: Assess role of ‘cyclical retrograde propagated contractions’ (CRPC) in constipation. 3. RA3.2: Develop novel MRI contrast agent. 4. RA3.4: Establish MRI methodology to evaluate portal hypertension. 5. RA3.5: Estimate hepatic glutathione flux using MRS. Medium term: 1. RA1.1: Develop integrated molecular/imaging-based algorithm to stratify HCV-related fibrosis. 2. RA1.1: Evaluate antiviral properties of ficolins. 3. RA1.2: Undertake proof-of-principle studies for C. difficile prevention/treatment 4. RA1.3: Test biomarkers and develop management strategies to balance Hp-related gastric/extra-gastric diseases. 5. RA2.1: Modulate CRPCs using 5HT3 antagonists. 6. RA3.1: Assess drug dissolution in-vivo using MRI. 7. RA3.3: Evaluate secretaogogues in cystic fibrosis. 8. RA3.5: Evaluate hepatic beta-oxidation using MRS. Long term: 1. RA1.1: Develop antibody-based HCV vaccine. 2. RA1.2: Trial most effective C. difficile therapies. 3. RA1.3: Develop mucosal-targeted liposomal delivery of anti-Hp therapy. 4. RA2.2: Assess enteroendocrine peptides in Crohn’s disease (CD). 5. RA2.3: Assess link between sarcopenia and fatigue in CD. 6. RA2.4: Evaluate efficacy of L-carnitine in non-alcoholic steatohepatitis (NASH). 7. RA2.5: Investigate urea cycle dysfunction in NASH. 8. RA3.4: Develop integrated molecular/MRI-based algorithm to distinguish inflammation from fibrosis in chronic liver disease. 9. RA3.5: Develop 23Na MRI to assess salt retention in cirrhosis.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: ORAL AND GASTROINTESTINAL
Title: Viability testing and transplantation of marginal livers
Funder: Wellcome Trust

Abstract: Health Innovation Challenge Award to Professor Darius Mirza, The University of Birmingham and University Hospitals Birmingham NHS Foundation Trust Liver transplantation is the only curative option for patients with end-stage liver disease. There are two types of cadaver organ donors; donation following brain death (DBD) and donation following circulatory death (DCD), the latter from patients with no prospect of recovery who have supportive treatment withdrawn. In DCD, the organs are exposed to an additional warm period without oxygen and therefore recipients have a higher risk of graft failure or complications. DBD donation is decreasing, so these DCD organs are a vital source, however a significant number are rejected due to their poor condition. Normothermic machine liver perfusion (NMLP) is a technique whereby a liver is perfused with a combination of blood and other fluids at the body's normal temperature. It aims to mimic the environment that a liver experiences in the body. We Professor Darius Mirza and colleagues at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust have discovered a technique that uses NMLP that enables clinicians to test the viability or function of the organ prior to transplantation, and thereby may reduce the risk of primary non-function for patients. This additional feature may also facilitate safer use of these higher risk organs. The key objectives of the research are to validate the protocol for viability testing of discarded donor livers, and increase the number of livers available for transplantation.


Research activity codes: 5.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL
Title: Gut Reaction - The Health Data Research Hub for Inflammatory Bowel Disease
Funder: Medical Research Council

Abstract: "The purpose of our proposed Hub is to integrate genomic data with structured phenotypic data and previously inaccessible routinely collected longitudinal healthcare data from a large cohort of patients recruited to the NIHR BioResource with the common immune mediated diseases Crohn’s disease and ulcerative colitis (collectively inflammatory bowel disease or IBD). The output will be a world-class, multi-dimensional integrated data resource for research and innovation; using a model based on open tools and data standards that could readily be scaled and replicated for other disease areas. Disease Focus: Why Inflammatory Bowel Disease (IBD)? IBD is common, affecting 0.78% of the population, and exacts substantial morbidity, frequent need for major surgery, and healthcare cost. Treatments increasingly focus on (expensive) antibody therapies, but responses vary substantially for poorly understood reasons. Many new IBD therapeutics are in development. Organisations involved: Building on the early successes of our Sprint Exemplar Innovation Project, our collaboration is between multiple NHS sites, academia and industry (listed in 1.1.2 above). Working in partnership with patients and the public, the UK IBD Registry and Crohn’s & Colitis UK, we will develop methodologies to link data assets from more than 25,000 patient participants of the NIHR IBD BioResource who have provided consent to access their medical records for research, and are undergoing genome-wide profiling. These participants are the cornerstone of our proposed Hub. Their detailed phenotype data is already captured and hosted at AIMES, a trusted aggregator of NHS data. Here it will be combined with: Digital pathology, diagnostic reports and images direct from NHS Trusts (ten sites initially) Health Episode Statistics (HES) from NHS Digital IBD Registry data Whole exome sequence data from the Wellcome Sanger Institute Services provided: Our goal is to facilitate research that will benefit patients by providing: production grade’' data and interoperability between platforms advanced data storage and analytical environments for managing multi-dimensional data at scale methods that support the highest standards of data discoverability, security, anonymisation andgovernance meta-data to the HDRUK National Innovation Gateway, to support discoverability and facilitateaccess. Exemplified by our partnership with AIMES (ISO27001 DSPTK level 2) and Privitar, as appointed by NHS Digital to develop national ‘De-ID’ solution, we will demonstrate the highest standards of data governance and, using the processing capability of Microsoft Azure, provide a scalable and replicable model for other NHS data assets."


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: ORAL AND GASTROINTESTINAL
Title: Disruption of a T cell recruitment and retention gradient for the treatment of chronic intestinal inflammation in inflammatory bowel disease
Funder: Medical Research Council

Abstract: Inflammatory bowel disease (IBD) is a highly heterogeneous disease necessitating a range of treatment options, especially for non-responders to existing therapies. The disease complexity also demands new treatments to improve limited response rates associated with the blockade of single cytokine or cell adhesion targets. In our work recently published in Cell, we used patient tissue biopsies to identify a pathogenic stromal population significantly expanded in active disease, secreting two major T cell chemoattractants, CCL19 and CCL21, which share functional redundancy in their ability to mediate the trafficking of CCR7+ T cells and mature dendritic cells (DCs). Our data indicate aberrantly activated stromal cells create a high lymphocyte-attraction and retention gradient, thus contributing to the chronicity of inflammation. Here we seek to disrupt the T cell recruitment/stimulation circuitry mediated by the CCL19/21-CCR7 axis. Blockade of CCL19/21 will also have an effect on antigen presentation in secondary lymphoid organs (SLOs), where mature DCs carrying microbiota-derived antigens will migrate towards the chemokine gradients. These gradients also balance the attraction versus egress of CCR7+ naïve and memory T cells to and from SLOs. As >60% of microbiotareactive T cells express high levels of CCR7, transient disruption of these ligand-receptor interactions will impair T cell priming in SLOs during in both acute and chronic phases of the disease, in addition to cutting off T cell homing to inflamed tissues with high ectopic CCL19/21 production. We will select CCL19/21 neutralising antibodies with cross-species reactivity and assess their functionality by T cell signalling and chemotaxis assays. Following functional validation, we will use an established chronic inflammatory murine colitis model to assess the effects of CCL19/21 blockade. Pre-clinical pharmacodynamics and efficacy data will then be used to inform subsequent clinical dosing regimen.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Microbiome mediated toxicity of drugs and other xenobiotics
Funder: Medical Research Council

Abstract: Drugs and other xenobiotics often pass through the digestive tract. Yet, how these compounds influence the gut microbiome and in turn get modified into potentially toxic products is known only in a few cases. Recent findings in this area have brought forward the fundamental role of the microbiome in determining drug efficacy, mode of action and side effects. The overarching goal of this research programme is to discover and model complex (xeno-) metabolic networks emerging in the gut microbiota and thereby gain mechanistic insights into microbiome-mediated toxicity. To this end, this interdisciplinary programme combines computational (metabolic modelling, bioinformatics, chemo-informatics and machine learning) and experimental (in vitro microbiomics, metabolomics and chemical genomics) approaches. The envisaged framework will lead to the development of effective intervention strategies to mitigate microbiome-mediated toxic effects with probiotic cocktails and small molecule antidotes. Furthermore, through leveraging the genomic and metagenomic data at individual level, the research will enable tackling microbiome-mediated toxicity in a personalised manner.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: MICA: Molecular drivers of fibrosis at the hepatic epithelial-mesenchymal barrier
Funder: Medical Research Council

Abstract: Chronic liver disease (CLD) results from unresolved damage. Background and preliminary investigations suggest that unresolved hepatocyte damage promotes inflammatory and fibrogenic cross-talk to resident mesenchymal cells (myofibroblasts) culminating in progression to cirrhosis. The goal of the research will be to illuminate the mechanisms by which unresolved hepatocyte stress stimulates fibrosis and in doing so unlock new therapeutic solutions and biomarkers for monitoring disease progression. Our overarching hypothesis is that unresolved hepatocyte stress promotes epigenetic and transcriptional reprogramming to establish a de-differentiated epithelium (i.e. hepatocytes) that stimulates fibrosis progression via soluble mediators that modulate myofibroblast phenotype and function. We will address this hypothesis by tackling three key objectives: 1. Discover mechanisms of hepatocyte epigenome and transcriptome remodeling that drive fibrosis. 2. Define hepatocyte-myofibroblast fibrogenic cross-talk pathways. 3. Unlock intercellular IL-1a/CCL2 fibrogenic signaling for therapeutic intervention in chronic liver disease. The 1st objective will employ a bespoke human liver bioreactor to model disease processes occurring in hepatocytes in NAFLD. Epigenetic and transcriptome adaptions to lipid stress will be mapped, functionally interrogated, validated in patients and translated to new blood-based diagnostics. In objective 2 we will discover how a novel regulatory pathway involving the transcription factors c-Rel, Snail and Twist operate in hepatocytes to establish a 'secretome' communicating fibrosis-stimulating signals to myofibroblasts and identify key regulatory components of the 'secretome'. Hepatocyte-derived IL-1a is one such component which in objective 3 we will study by genetic approaches as a potent stimulator of myofibroblast-monocyte fibrogenic signaling.


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