NIHRDataInsights/HRCSData huggingface dataset:
Title: Decoding Yes Associated Protein 1 driven hepatic stellate cell activation
Funder: Guts UK

Abstract: Fibrotic disease causes a huge social and economic burden. As many as 45% of deaths can be attributed to fibrotic disorders. The ageing population and the global obesity epidemic are causing the socio-economic burden of fibrosis to increase, and there are still no approved anti-fibrotic therapies. There is therefore an urgent need to better understand fibrotic disease processes to identify novel therapeutic targets. Fibrosis caused by liver injury is driven by hepatic stellate cells (HSCs) that alter their phenotype (activate) from quiescent lipid rich, vitamin A storing cells, and become proliferative, migratory, contractile cells that secrete the proteins that make up the fibrotic scar. Our previous work showed that mechano-sensitive signalling via Yes Associated Protein 1 (YAP1) drives and maintains the fibrotic response of HSCs to liver injury. This project will use bioinformatics and candidate driven approaches to identify pro-fibrotic YAP1 targets. This will identify new targets for the development of urgently needed anti-fibrotic therapies. Critically, this project will generate cutting-edge data to support James Pritchett’s future research grant applications. e.g. New Investigator Research Grant targeting the MRC Molecular Medicine Panel: “Using YAP1 to identify novel targets for anti-fibrotic therapies”.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: FAecal microbiota transplantation in primaRy sclerosinG chOlangitis
Funder: PSC Support

Abstract: FAecal microbiota transplantation in primaRy sclerosinG chOlangitis: The FARGO trial This study will test the safety and long-term effects of FMT as a treatment for people with PSC. It will also improve understanding around which specific micro-organisms in donor stool are most important, and how this information can be used to enhance the product for large scale rollout. Researchers will randomly allocate individuals with PSC to receive either FMT once a week for 8 weeks (group 1), or placebo (an inactive FMT equivalent; group 2). Each group will continue to receive routine standard of care for symptoms and treatment for their IBD. Both groups will be observed for another 40 weeks, meaning the trial will run for 48 weeks. The team will then measure how successful the treatment has been in improving liver blood test results, the burden of scarring in the liver, activity of IBD and quality of life.

Lay abstract: as per abstract

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Developing a Quality of Life Tool in PSC
Funder: PSC Support

Abstract: The aim of this project is to set out plans to progress a PhD, based at the University of Hertfordshire (UH), that will aim to take forward the body of work completed to date by Dr Elena Marcus. The research by Dr Marcus aimed to work towards a PSC specific Quality of Life Measure (QoL). This was to recognise the unique patient experience and priorities that may not be captured in health general QoL measures. Dr Marcus has contributed to the development on refinement of an initial item list that could form part of a QoL assessment, but this is yet to undergo the degree of validation to support its wider use amongst researchers, regulators and or in clinical practice settings. This will lead to the first PSC-QoL that will be available translated with rigour, and tested for use in a range of cultural contexts.

Lay abstract: as per abstract

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.1 INDIVIDUAL CARE NEEDS
Health categories: ORAL AND GASTROINTESTINAL
Title: Development of a Method for the Creation of Artificial Teeth for Training Dentists
Funder: Barts Charity

Abstract: Within dental education, there is a distinct need for hands-on pre-clinical training before a patient?s treatment is carried out for the first time. A combination of extracted teeth and artificial teeth (typodonts) are widely used. However, the availability of extracted teeth is low, and there is dissatisfaction amongst undergraduate dental students that these artificial teeth do not look and feel like extracted teeth. In his successful PhD project, Alexander Cresswell-Boyes (ACB) demonstrated that artificial teeth required between two to four times the cutting force compared to natural teeth. He then went on to develop 3D-printable resin composite materials that matched the real cutting force and used these to print morphologically accurate typodonts from micro-CT scans of real teeth. Trials with students and clinicians have been very favourable, but further improvements could be made. It would be difficult to monetize this development and the best way to ensure that this work is not wasted is to make it available to dental schools everywhere. However, without access to specialised milling and sieving equipment, production of ACB?s composite resins would be impossible. In the proposed project, we will address feedback concerning enamel feel and occasional fragility and investigate the durability of the typodonts under different storage conditions. We will also investigate alternative filler materials that are readily available, to obviate the need for milling and sieving. Following this, we will develop instructional content for the complete process of resin-filler mixing, 3D printing and typodont assembly, then invite other dental schools to evaluate both their use and manufacturing process. Finally, this instructional content will be hosted on a freely accessible website.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigating the role of CTHRC1 in biliary fibrosis
Funder: Wellcome Trust

Abstract: Fibrosis (scarring) is a necessary part of regeneration, a stable scaffold around which cells can reorganise themselves to regain function is essential. In the liver, there are different modes in which fibrosis occurs, we need to learn more about what makes them different.844 million people worldwide have chronic liver disease, with about two million deaths per year. Chronic liver disease can progress to cirrhosis, liver cancer and death. Treatment is limited to removal of the underlying cause or liver transplantation. Importantly, the greater the fibrosis a patient has the poorer the outcomes. Therefore, developing antifibrotic therapies for patients with chronic liver disease will impact significantly on morbidity and mortality. Primary biliary cholangitis (PBC) is a chronic liver disease resulting in destruction of the bile ducts. We have identified a protein called CTHRC1, expressed on scar-forming cells surrounding the duct, in patients with PBC. These cells play a role in fibrosis and disease progression.To investigate how CTHRC1 contributes to liver fibrosis in PBC I will use liver tissue and cells from PBC patients and mouse models of liver fibrosis to explore whether targeting the function of CTHRC1 could be a new treatment for patients with liver fibrosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Beyond GWAS: Exploring complex disease with WGS and scRNA-seq
Funder: Wellcome Trust

Abstract: Inflammatory bowel disease (IBD) is a disease of the gut affecting over 2.5 million people in Europe alone. Through genome-wide association studies, over 240 genomic regions have been identified as significantly associated with the disease or its two subtypes: Crohn’s disease and ulcerative colitis (1,2). However the mutations, genes and cell-types that drive disease progression, are still unknown and for many patients, IBD remains incredibly difficult to treat. The Anderson group has undertaken two distinct, large-scale projects in an effort to fill in many of the gaps in existing knowledge. Firstly, whole genome and exome sequencing of large cohorts of healthy and diseased individuals is being undertaken to better understand the disease-associated regions. During my PhD I will use this data to examine the effect that deletions, insertions and inversions of large chunks of DNA can have on IBD. The second major ongoing project is single-cell sequencing of terminal ileum, rectal and blood samples taken from healthy individuals and patients with Crohn's disease. In the second half of my PhD project, I will use the single-cell data to determine the genes, pathways and cells involved in Crohn’s disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Determining the function of intestinal macrophage subsets in health, inflammation and repair
Funder: Wellcome Trust

Abstract: Intestinal macrophages are crucial in maintaining gut homeostasis and, during health powerful regulatory mechanisms exist to maintain intestinal macrophages in an anti-inflammatory state, allowing them to exist in their antigen- and microbe-rich environment. However, macrophages are now also considered key drivers of intestinal pathologies, such as inflammatory bowel disease (IBD). Moreover, proinflammatory macrophages accumulate in the intestine and promote reduced epithelial-barrier integrity in response to distant inflammation, including cerebral ischemia (stroke). How macrophages can play such seemingly paradoxical roles remains unclear. One line of thought is that functionally-distinct macrophages subsets may dominate in certain contexts, i.e. health, inflammation and repair. Recent work from our lab uncovered at least two transcriptionally-distinct intestinal macrophage subsets, however their locations and functions within the gut wall in different contexts remain unclear. I aim to determine the roles of these macrophage subsets in intestinal inflammation caused by local insult or distant injury, as well as tissue repair. I will use immunofluorescence and flow cytometry together with novel genetic depletion models to assess the spatial and functional characteristics macrophage subsets in experimental IBD and intestinal inflammation caused by cerebral ischemia. These studies will determine whether the paradoxical roles of intestinal macrophages are explained by functional heterogeneity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Improving engraftment for cell therapy in cholangiopathies
Funder: Wellcome Trust

Abstract: The cholangiopathies are a group of diseases, which cause injury to the biliary system. The most prevalent of these are primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC), both of which frequently progress to cause hepatic failure. Liver transplant offers the only curative therapy for PSC and PBC however, there are a limited number of livers available and transplantation is associated with a significant risk of complications. Stem cell therapy has shown promise as an alternative treatment strategy, but delivery of cells to the biliary system is challenging. Recently it has become possible to create particles which target specific markers in tissues and cells. Particles designed to target the biliary system can be attached to the surface of stem cells, creating a method for stem cells to home to the biliary system, in the hope of improving cell delivery and treatment efficacy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Treatment of periodontal bony lesions with minimally-invasive non-surgical treatment for prevention of tooth loss
Funder: Barts Charity

Abstract: Severe periodontitis (gum disease) is the sixth most common disease worldwide and the most common reason for tooth loss. This study proposes to test a new minimally-invasive intervention for the treatment of deep defects to the bone around teeth (?intrabony defects?), which are associated with rapid disease progression and are usually treated surgically. We have recently proposed the use of a new treatment strategy, minimally-invasive non-surgical periodontal treatment (MINST), for the treatment of these defects, showing favourable clinical results in a preliminary study, but without direct comparison with the standard surgical treatment. Hence, we propose a 15-month clinical study comparing MINST with surgical treatment for gum disease. The main outcome will be bone re-growth. Results of this study could represent the first strong evidence for the wider use of MINST for severe gum disease, with considerable patient benefits as well as reductions in morbidity and NHS costs.


Research activity codes: 5.3 MEDICAL DEVICES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Small bowel soft robotic motile enteroscope (SOFTIE)
Funder: Wellcome Trust

Abstract: Difficulties in establishing diagnosis of small bowel (SB) disorders, prevented effective treatment. This problem was resolved by rigid wireless capsule endoscopy (WCE), which rapidly became the gold standard SB investigation in routine clinical practice. Patients are required to swallow the WCE pill, which tumbles down and provides imaging of the inside of the SB. Despite their benefit, WCE has several limitations: the lack of active locomotion can result in incomplete examination, capsule retention and impaction within strictures. The SOFTIE project aims to replace the rigid WCE with a soft segmented narrower mini-robot (easier to swallow) with intrinsic locomotion produced by vibrating motors. SOFTIE will be equipped with HD CMOS camera imaging system with LED-lighting, enabling full and complete enteroscopy. In the small bowel SOFTIE will rely on its on-board power supply and RF communication with a wireless external portable console. SOFTIE will avoid all the documented complications of WCE devices. Prof Sir Alfred Cuschieri and his engineering team at the Institute for Medical Science and Technology (IMSaT), assisted by two clinical colleagues at Ninewells Hospital, Dundee (Mr Afshin Alijani and Dr Craig Mowat) will produce a proof of concept working prototype which will undergo testing by experiments in an in-vitro porcine small bowel model'

Lay abstract: Difficulties in establishing diagnosis of small bowel (SB) disorders, prevented effective treatment. This problem was resolved by wireless capsule endoscopy (WCE), which rapidly became the gold standard SB investigation. WCE pills are large rigid capsules, which the patient swallows and provide endoscopy of the SB. Despite their benefit, WCEs have several limitations: lack locomotion, resulting in incomplete examination, capsule retention and impaction within strictures. This project will substitute WCEs with a soft segmented thinner robot with intrinsic locomotion produced by vibrating motors on the SB mucosal surface. Also, SOFTIE will develop dual CMOS camera imaging system with LED-lighting, elastomeric ferromagnetic skin (for dislodgement of any impaction by external magnetic probe), detachable power tether, on-board RF communication with a wireless portable console. SOFTIE will guarantee complete small bowel endoscopy and avoid all the documented complications of WCE devices. On completion, the project will enable synchronous small bowel endoscopy and descending colonoscopy.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigation of antifibrotic targets in human liver fibrosis using a single cell transcriptomics approach.
Funder: Wellcome Trust

Abstract: Liver fibrosis is a major global healthcare burden. Iterative liver damage, secondary to any cause, results in progressive fibrosis, disrupted hepatic architecture and aberrant regeneration, defining characteristics of liver cirrhosis. Currently, treatment options for patients with chronic liver disease are limited to removal of the underlying cause, if possible, or liver transplantation. However, demand for transplantation greatly outweighs donor organ supply. Therefore, effective antifibrotic therapies are urgently required. To enable true precision medicine-based therapies, we need to significantly increase our understanding of the cellular and molecular composition of the fibrotic niche across the different forms of human liver fibrosis, and therefore this application is deliberately human disease-focused. In this proposal, we will define and interrogate the interactome of the human liver fibrotic niche using cutting-edge single-cell transcriptomic approaches including single-cell and single-nucleus RNA sequencing, spatial transcriptomics and machine learning, and single-cell epigenomics. These studies should greatly advance our understanding of how the fibrotic niche operates across different forms of human liver fibrosis, generating aetiology-specific, relevant and potentially druggable therapeutic targets to treat patients with liver fibrosis. By the end of this Fellowship, if awarded, we aim to have multiple therapeutic targets entering Phase I clinical trials.

Lay abstract: Liver fibrosis (scarring) is a major healthcare burden. Repetitive liver damage, secondary to any cause, results in progressive fibrosis, eventually leading to cirrhosis. Currently, treatment options for patients with chronic liver disease are limited to removal of the underlying cause, if possible, or liver transplantation. However, demand for transplantation greatly outweighs donor organ supply. Therefore, effective antifibrotic therapies are urgently required. To enable development of antifibrotic drugs, we need to increase our understanding of how the human liver scars. We will use a cutting-edge approach, single-cell transcriptomics, which allows measurement of gene expression levels across thousands of individual cells enabling the identification of scar-forming cells and molecules. This research should greatly advance our understanding of human liver scarring, generating relevant, potentially druggable therapeutic targets to treat patients with liver fibrosis. By the end of this Fellowship, if awarded, we aim to have multiple therapeutic targets entering Phase I clinical trials.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining Determinants of Intestinal Barrier Health and Disease
Funder: Wellcome Trust

Abstract: IBD affects over 1.5 million and 2 million people in North America and Europe respectively. A significant proportion fail to respond to current treatments. In IBD genetic, environmental and intestinal barrier defects combine to precipitate dysregulated immune responses in the mucosa that manifest in disease. Recently we have utilized single cell technologies to chart the behaviour of diverse cell types making up the mucosal barrier in health and early diagnosis IBD. This has demonstrated the nature of cellular remodeling occurring in the human colon in inflammation revealing trajectories of differentiation, the connectedness of different cell states together with describing novel epithelial, mesenchymal, T, B and myeloid cell states that hallmark disease. In this work we will build on these findings to explore functional pathways and barrier cell relationships revealed by this analysis that maintain commensal symbiosis in health but lead to breakdown in tolerance driving inflammation in IBD. Specifically, we will focus on defining how the colonic epithelia remodels to lose cell intrinsic barrier protective function, how the supporting mesenchyme fuels inflammation and how heterogenous colonic myeloid cells handle commensal bacteria in health and IBD to drive aberrant adaptive responses.

Lay abstract: Cells lining the wall of the intestine play precise roles coordinating nutrition and health. These specialised cells interact with adjacent stromal and immune cells to create a protective barrier between luminal microbes and the mucosal immune system. Cells making up this niche are diverse and their individual contribution to barrier health remains obscure. Inflammatory bowel disease is a debilitating disease where defects in the intestinal barrier are believed to drive inflammation. We will use a range of experimental approaches to define molecular determinants of barrier health. We will study the relationships between individual intestinal lining cells, structural supporting cells and immune cells in health and inflammation to define aspects of barrier physiology that break down in IBD. Our findings will provide new avenues for interventions that promote barrier health or treat inflammation.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Colon Kit: Feasibility assessment of production scale-up for an integrated model of the human large intestine
Funder: Innovate UK

Abstract: This project aims to assess the feasibility of scaling up production of a 'Colon Kit' a research model of the human large intestine. This will meet the pressing need for effective and affordable models of the human large intestine for research and personalised medicine. This product can provide an accessible, and affordable cutting edge research tool for labs. The product also has diagnostic and prognostic potential. The tool can be used to carry out patient specific investigations and treatment screens to better identify effective treatments. The Human Microbiome Market is valued at $376.3 Million (2019) with CAGR of 21.8% from 2020 to 2027 (VMR, 2019). The importance of the microbiome to health and disease is increasingly recognised, and health and pharmaceutical product development aims to address this need. Aelius Biotech?are a research organisation who specialise in lab models of the digestive tract, offering a range of research tools to help understand and develop formulations to improve and de-risk product development and get successful products to market. Aelius has developed and tested an early-stage prototype integrated large intestinal model -- the first of its kind that includes a cell culture system that integrates modelling of the intestinal mucus bi-layer and epithelium with the microbiome. This has potential to be a huge development in digestive modelling providing the first system capable of modelling luminal, mucus and epithelial phases of digestion in a continuous, integrated system from mouth to terminal large intestine. This project aims to make this technology accessible globally to research labs. This proposed feasibility project would draw on the expertise of CPI in 'design for manufacture'. CPI as part of the High Value Manufacturing Catapult will investigate feasibility of design and manufacturing options, trial and comparison to current state-of-the art to ensure that the device meets industry needs, is usable and is acceptable to users, thereby increasing the likelihood of adoption by customers. The project includes validation of the model with commercial products to generate case studies and validation data to promote the model.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: ORAL AND GASTROINTESTINAL