NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterisation of genotype-molecular phenotype interactions to provide a platform for genetically validated drug discovery and development in NAFLD
Funder: Medical Research Council

Abstract: Non-alcohol related fatty liver disease is a common cause of abnormal liver function tests and end-stage liver disease. The condition demonstrates significant clinical heterogeneity including variable association with features of the metabolic syndrome, disease stage and subsequent progression. There are no therapies currently licensed for the condition, several potential agents have failed in late-stage clinical trials. The use of genetics to identify drug targets and prioritise candidate therapeutic agents for development is a proven means to increase the likelihood of subsequent approval. NAFLD is a polygenic disease and recent studies have identified a number of genetic risk loci, however the links between these genetic variants, gene function or expression and ultimately disease causation are not clearly understood. GlaxoSmithKline and Imperial College London will partner on this project through the exchange of clinical, academic and industrial expertise and resources. The project will use state-of-the-art image analysis and spatial transcriptomic techniques to precisely characterise, at a single cell resolution, the expression profiles present in the livers of patients with different stages and phenotypes of NAFLD. This rich dataset will be used to understand genotype-phenotype interactions in NAFLD in order to provide a platform for both discovery and validation of putative drug targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: MICA: Optimisation of prolonged normothermic liver machine perfusion and assessment of its feasibility to provide extra-corporeal liver support
Funder: Medical Research Council

Abstract: Background Liver preservation by normothermic machine perfusion (LNMP) increases organ utilisation for transplant. Although current devices are licensed for 24-hour perfusion, 7-day perfusion appears experimentally feasible. Beyond its utility in transplantation, prolonged NMP may enable a perfused liver to provide temporary extra-corporeal liver support through connection to patients with acute and acute-on-chronic liver failure (ALF). As NMP-preserved livers retain a range of liver functions, this system may reduce mortality where others have failed. Aims P1: Optimisation of LNMP to support 7-day perfusion. P2: Assessment of capacity of prolonged LNMP to provide Biological Liver Support (BLS). P3: Determination of optimal interface between patient and BLS circulations. Methodology A porcine model of Donation by Circulatory Death will be used to procure livers for NMP. P1: 3 interventions will be tested for their potential to prolong LNMP: a) Incorporation of high molecular weight cut-off dialysis. b) Red blood cell (RBC) rejuvenation therapy. c) Omega-3 polyunsaturated fatty acid-enriched nutrition. P2: The capacity of an NMP-liver to reproduce liver function will be quantified through assessment of lactate, ammonia, ICG clearance and factor V synthesis. The ability of an NMP-liver to remove the damage-associated molecular patterns released by a failing liver will be measured in an ex situ model of the BLS set-up. A healthy NMP-liver ('BLS') will be connected to a second NMP-liver, induced to fail through paracetamol overdose ('patient'). P3: The same model will assess the effect of whole-blood versus plasma-only exchange between the 'patient' and 'BLS' circulations on RBC mixing, immune response and functional capacity. Future Plans Prolonged LNMP will improve transplant logistics, viability testing and pre-implantation therapeutic delivery. Parts 2 and 3 will provide proof-of-principle for an efficacy study in a porcine ALF model.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL
Title: In-Silico Modelling and 3D-printing of Dental Implants with Photo-active and Infection-Resistant Coatings (PERIo-Dent-ItiS)
Funder: Medical Research Council

Abstract: The proposed secondment is a collaboration between the University of Leeds and Attenborough Dental (AD) in Nottingham. AD aims to demonstrate a novel 3D-printing and additive manufacturing process for new generations of dental implants. These implants are targeted to minimize the risk of infection, which causes the peri-implantitis, which is often observed in 10-15% of patients with implants. In the case of peri-implantitis, the implants fail due to loosening. The symptom also occurs in combination with the prevalent bacterial infection around the implant surface where the acidic fluid slowly resorbs healthy bone. The bone resorption may accelerate under the chewing and mastication. Currently, there is no long-term solution for early detection of the onset of bacterial infection until the pain starts, which implies that the infection has spread and surgical intervention might be necessary, depending on the acuteness of peri-implantitis. The number of cases of peri-implantitis is rising at 6% per annum in the 50+ years age group. A solution must be found which must be able to minimize the risk of peri-implantitis by improving the implant design. The industrial secondment at AD aims to demonstrate a new paradigm in implant manufacturing by transferring the knowledge from UoL and by building a co-creation approach for manufacturing via research in the following areas: a) by providing CAD implant design which will be porous instead of solid Ti-alloy. Novel design will offer a much better opportunity for implant-tissue integration; b) by designing biomechanically robust implant which in the oral acid condition does not fail and curtails bacterial infection; and c) by forming infection resistant film on the implant which protects against bacterial infection, and allows blood vessels to grow inside and around the porous implant for minimizing infection. AD will benefit from knowledge exchange during the secondment by training a person for industry.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL
Title: Research Methods for Implementing Infection Quality Control for Dental Implants (IQ-ReMDI).
Funder: Medical Research Council

Abstract: Aim: To develop and implement a peri-implantitis model to evaluate implants. Methods for Implementation: The lead applicant has previous success in developing a robust periodontitis biofilm model (doi: 10.1038/s41598-019-41882-y), where dental plaque samples from healthy volunteers were cultured on inert surfaces under nutritional conditions that reflected periodontal inflammation and which consequently shifted the microbial population to that found typically in periodontitis. This approach can easily be adapted to modelling conditions leading to peri-implantitis, and can be used as a tool to test the anti-microbial properties of implant materials. This approach is unique in that no complex microbial system has yet been used for implant applications. Our approach will be to develop an efficient microbiological system for implant characterisation that is suitable for use in a commercial environment, paving the way for further collaboration post-secondment. We will certify implants that achieve a clear reduction of peri-implantitis-associated microbiota over time ontheir surfaces, so they can be brought further towards commercialisation. We will undertake investigations in parallel for achieving our aim.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL
Title: Therapeutic Targeting of Pathogenic Scar-associated Macrophages in the Fibrotic Niche of Chronic Liver Disease
Funder: Medical Research Council

Abstract: Liver disease affects 844 million people worldwide resulting in 2 million deaths per year. With a rising incidence and a lack of new effective treatments in most cases, it is predicted that liver disease will soon become the commonest cause of premature death in the UK. Irrespective of the cause of liver disease, chronic damage to the liver results in fibrosis. The degree of fibrosis is the best predictor of adverse clinical outcomes, meaning there is great interest in developing novel antifibrotic therapies to prevent disease progression. Our previous work has shown that a specific subpopulation of scar-associated macrophages (SAMac) are key regulators of liver fibrosis. Hence, therapeutic targeting of SAMac represents an attractive novel therapeutic strategy. In this Fellowship, we will couple cutting-edge mutiomic data and computational approaches with new experimental models, to dissect the biology of SAMac at previously unprecedented resolution and enable the identification and functional testing of candidate antifibrotic therapeutic strategies. This will be achieved by completing 3 main aims: 1) Dissect the phenotype and microenvironmental niche of SAMac during early-stage human liver disease 2) Define phenotypic differences in SAMac between progressive and resolving liver fibrosis 3) Functionally assess candidate antifibrotic therapeutic targets to modulate SAMac The proposed experiments will harness the power of single-cell RNA-sequencing and spatial transcriptomics on fibrotic liver tissue from both humans and mice, to resolve the phenotype of SAMac and interrogate intercellular signalling networks during progressive fibrosis. Candidate target molecules will be functionally assessed using high-throughput in vivo CRISPR screens and antifibrotic efficacy tested using mouse models and human liver organoid cultures. Ultimately, I anticipate identifying new antifibrotic therapeutic strategies which can then be tested in patients with chronic liver disease


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: HDHL MICA GENETIC CARBOHYDRATE MALDIGESTION AS A MODEL TO STUDY FOOD HYPERSENSITIVTY MECHANISM AND GUIDE PERSONALISED TREATMENT USING A NON-INVASIVE
Funder: Medical Research Council

Abstract: Food intolerance (including food aversion) accounts for most adverse food responses, affecting an estimated 20% of the population. In irritable bowel syndrome (IBS), which affects 1 in 10 people, the reported prevalence of food intolerance is as high as 80%. Team members have identified a subset of "organic" IBS who carry hypomorphic (defective) sucrase-isomaltase (SI) gene variants. This carbohydrate malabsorption is characterized by diarrhea, abdominal pain and bloating, which are also features of IBS. Similarly, to the congenital SI deficiency (CSID), these SI variants (Phe15Val) are characterized by reduced in vitro disaccharidase activity. Expected prevalence of single and double carriers for this variant, in those with the European ancestry, are 40% and 10% respectively. These observations suggest that DNA variation in the SI gene affects the risk of carbohydrate malabsorption in a continuum, ranging from mild IBS-like forms to fully blown severe CSID. Until recently the only technique available for mechanistic carbohydrate maldigestion studies was the breath test. The principle is that hydrogen and/or methane is produced, and a rise detected in the breath, if the tested carbohydrate reaches fermenting bacteria before being digested/absorbed in the small bowel. These tests do not indicate whether gas production takes place in the small bowel and/or the colon. Nor do they indicate whether other factors like gut distension or intraluminal water content play a role in symptom generation. Members of our team have developed a multiparametric magnetic resonance imaging (MRI) platform which has been successfully utilised to study IBS. We propose a three-component study to assess: the prevalence of gene variants predisposing to carbohydrate malabsorption in a large number of IBS patients; their in vitro functional characterization; and their in vivo mechanistic consequences using MRI.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: MRI-based technologies for the assessment of patients with non-alcoholic fatty liver disease [DAP59]
Funder: Department of Health and Social Care

Abstract: Non-alcoholic fatty liver disease (NAFLD) includes a range of conditions that are caused by a build-up of fat in the liver and have not been caused by alcohol consumption. This build-up of fat can cause inflammation and persistent inflammation can cause scar tissue to develop. This scarring is called fibrosis. Severe fibrosis can cause permanent liver damage (cirrhosis), which can lead to liver failure and liver cancer. Patients with NAFLD undergo tests to identify whether they have fibrosis. Tests are not always accurate and multiple tests can give conflicting results. Some of the tests currently used in the NHS to detect fibrosis may not be suitable for patients who are obese or who have a very high body mass index._x000D_ _x000D_ It is estimated that between one in three and one in five people in the UK have early stages of NAFLD. Risk factors for NAFLD include type 2 diabetes, high blood pressure or high cholesterol, and being overweight or obese. Current guidelines recommend using the Fibrosis-4 (FIB-4) test, the NAFLD fibrosis score (NFS) test or the enhanced liver fibrosis (ELF) test to assess level of liver fibrosis. If test results are unclear further tests are needed and these include transient elastography (TE), acoustic radiation force impulse (ARFI) and the ELF test (if not previously carried out). In current NHS practice, a liver biopsy may be offered to patients whose test results are inconclusive or conflicting or for whom the use of TE or ARFI is not suitable._x000D_ _x000D_ LiverMultiScan is imaging software that is used alongside magnetic resonance imaging (MRI). It provides quantitative analysis of liver fat content, liver iron concentration and fibro-inflammation. LiverMultiScan protocols can be built into existing abdominal MRI protocols._x000D_ _x000D_ Magnetic resonance elastography (MRE) is used in some NHS centres to assess liver fibrosis; however, MRE requires more equipment than just an MRI scanner._x000D_ _x000D_ This project will explore whether LiverMultiScan and MRE can be used to assess patients with NAFLD, and will consider whether use of these technologies will offer good value for money to the NHS.

Lay abstract: The purpose of this assessment is to explore whether two non-invasive magnetic resonance imaging (MRI) based technologies, specifically LiverMultiScan and magnetic resonance elastography (MRE), can be used to assess non-alcoholic fatty liver disease (NAFLD) and whether use of these technologies represents a cost effective use of NHS resources compared to a diagnostic pathway that does not include them.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Non-surgical management of Eosinophilic oesophagitis
Funder: Department of Health and Social Care

Abstract: Unlike many conditions considered within gastroenterology, Eosinophilic Oesophagitis (EOE) was only first described in the 1990s in children. Now, it is known to be the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults, with over 20,000 otherwise healthy people affected in the UK alone. Given the short time since recognition, it is not surprising that treatments are not established and instead research growing rapidly. A cochrane review in 2010 found 3 Randomised trials. In the last 4 years, European and USA national guidelines have been released demonstrating many more studies currently, but a scoping search and discussion with experts have highlighted many more studies since then, including some novel, but high cost therapies. There is a need for a thorough synthesis of all available medical therapies to support UK and international guideline updates. The use of the Cochrane format will be vital, as current synthesis are out of date, impacted by significant methodological deficiencies or both. A technical review by NICE released in June 2021 considers the oldest class of medications for this condition and so stakeholder colleagues from the British Society of Gastroenterology, as well as international colleagues and societies have asked for this update to be expedited.

Lay abstract: See Plain English Summary

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Probiotics for functional constipation in childhood
Funder: Department of Health and Social Care

Abstract: Between 10-20% of children have chronic functional constipation. Current mainstay therapies are laxatives. Our group previously received an incentive grant to update a review on laxative therapies in childhood constipation. This has been used in over a dozen international guidelines since its publication. Whilst these therapies have evidence to support their use, the effect sizes and numbers needed to treat suggest the need for alternative or additional therapeutic options._x000D_ _x000D_ The NICE guidelines for constipation in childhood, updated in 2017, did not find specific evidence to support the use of probiotics in childhood chronic constipation. However, the leading international guidelines in the last 5 years explicitly stated that probiotics are an area of interest with many ongoing studies that requires synthesis and the head of European gastroenterology society committee in this area has approached the group to ask for this review to be expedited. _x000D_ _x000D_ Scoping searches demonstrate that since our 2016 publication there are just 3 further trials of laxatives in children, but a further 6 trials of probiotics. Therefore, this represents the currently most studied area of interest within the field and the findings will direct impact UK and international guidelines and most importantly children using the NHS

Lay abstract: See summary

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigating mitochondrial dysfunction in determining the innate colonic epithelial phenotype in Ulcerative Colitis (UC): Developing a cell-based gut repair approach using human organoid technology.
Funder: Chief Scientist Office, Scotland

Abstract: Ulcerative colitis (UC) is a relatively common condition affecting the large bowel where the gut lining becomes very inflamed. A flare up of UC can have a significant impact on their quality of life and can lead to emergency surgery to remove their colon. In our study, we think that the mitochondria in the gut stem cells that replenish the gut lining may play a important role in UC. Mitochondria, primarily act to produce energy ‘cell batteries’. In the gut (particularly in UC), the mitochondria can be damaged after exposure bacteria and toxins. If the mitochondria become damaged in the gut stem cells, they can be passed on as cells divide, eventually the entire gut lining will have ‘faulty batteries’. We will study this by growing small sections of the human gut lining (‘mini guts on the dish’), with cells from individuals with and without UC. In particular, we will investigate how mitochondria can cause the gut lining and epithelial cells to fail and how we might correct this with drug treatment. One day, we may be able to grow healthy gut cells to replace and repair the damaged gut lining in UC as a treatment (‘replacing the faulty batteries’


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: PREdiCT- The Prognostic Effect of Enviornmental Factors in Crohn's and Colitis
Funder: Chief Scientist Office, Scotland

Abstract: Inflamatory bowel disease is a common cause of chronic ill-health among young peopl ein Scotland. The major forms of IBD, namely Chron's disease and ulcerative colitis, all too often confer a lifetime of unpleasent, intrusive and potentially dangerous burden of intestinal inflamation on individuals. Typical symptons include abdominal pain, diarrhoea, weight loss and lethagy. These adversely affect schooling, work attainment, pysoco-social well-being and sexual health. IBD costs the NHS £720 million per year, based on an average patient cost of £3,000; half of the costs are attributable to relapsing patients. Health expenditure is shifting from hospitalisation and surgery to medical therapy. However, existing modalities remain limited by lack of efficacy, unaccaptable toxicity and poor patient acceptability. Major surgical intervention is frequently required, with a high risk of recurrence and there is an increased risk of cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining How Cilia Loss Alters The Inflammasome In Polycystic Liver Disease.
Funder: Chief Scientist Office, Scotland

Abstract: The bile ducts are biological tubes within the liver. They transport bile from the liver to the intestine, where it helps digestion. Polycystic liver disease occurs when people have mistakes in their DNA, which affects how cells make bile ducts. Instead of making tubes, these cells make large, spherical-shaped cysts. These cysts are found throughout the liver and patients with these liver cysts have a swollen stomach, live with high levels of pain and increased chance of cysts rupturing and becoming infected. Currently, there is no cure for these cysts and only by understanding how they form and grow will we be able to develop effective treatments. Most of the DNA mistakes that cause polycystic liver disease affect a part of the cell, called the cilium, which protrudes from the top of the cell to sense the local environment. My work leading to this project has shown that when we remove cilia from bile duct cells livers develop cysts. We have found that after cilia-loss, cystic cells start communicating with immune cells, which normally make sure that your body is protected against infection. In this project, I will study how cysts talk to immune cells. To do this, I will first develop a system where we can grow cells in a dish and introduce DNA mistakes to see how they change the cilia. I will then look to see if these DNA mistakes cause cystic cells to send out more signals that interact with the immune system. Once I have identified whether DNA mistakes change the cilia and whether this changes which immune signals are sent out by cyst cells, I will add immune cells to dishes containing my cyst cells and determine whether the signals produced by cyst cells cause immune cells to move towards them. I will also define whether cyst cells cause changes in the immune cells that enable them to support the growth of cysts. Finally, I will use this system to test whether new medicines can be used to stop immune cells from talking to cyst cells to stop cyst growth. By the end of this project, I hope that I will have established a system which can be used to understand how cyst cells talk to immune cells and identify new ways to prevent cyst growth. These findings will allow me to move to the next stage of my career and study cystic diseases more


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