NIHRDataInsights/HRCSData huggingface dataset:
Title: Infection, Immunology and Translational Medicine - 'Control of intestinal immunity by the autophagy protein ATG16L1'
Funder: Wellcome Trust

Abstract: Autophagy is a process of recycling intracellular components in response to starvation or stress. It is also involved in clearance of defective organelles, intracellular pathogens and protein aggregates. Polymorphisms in autophagy genes were recently associated with susceptibility to inflammatory bowel disease (IBD); however the mechanisms responsible for this correlation remain unclear. Clinical and experimental evidence suggests that autophagy maycontribute to intestinal homeostasis in several ways, through distinct effects in intestinalepithelial cells and haematopoietic cells. The aim of this project is to test the hypothesis that autophagy contributes to intestinal homeostasis by influencing antigen presentation and inhibiting excessive proinflammatory responses in haematopoietic cells. Therefore, mice will be generated in which the autophagy pathway is selectively ablated in distinct haematopoietic cell lineages. Several complementary models of IBD will be employed to elucidate the functional consequences of autophagy defects in the context of intestinal inflammation. In parallel, in vitro approaches will be applied to characterize the impact of impaired autophagy on cellular physiology, bacterial handling and inflammatory responses in haematopoietic cells. Together, these experiments should identify mechanisms through which the autophagy pathway intersects withother immune pathways in the gut to regulate tissue protective and inflammatory responses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Scottish Consortium Translational Medicine and Therapeutics Programme: 'Bone marrow derived cell therapy to enhance regeneration of the liver following resection'.
Funder: Wellcome Trust

Abstract: In the UK the incidence of chronic liver disease is increasing exponentially, along with this has come a rise in the incidence of hepatocellular carcinoma. The treatment for this is resection of the portion of the liver containing the tumour. While the normal liver can regenerate following resection of up to 75% of its volume, regeneration of the fibrotic or cirrhotic liver is impaired. Cell therapies offer much promise in stimulating liver regeneration. The macrophage has been shown to be a key mediator in liver regeneration capable of promoting hepatocyte proliferation, activating hepatic progenitor cells and remodelling liver parenchyma. This project aims to explore the potential of macrophage therapy in the setting of liver fibrosis and partial hepatectomy using preclinical models.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Clinical PhD Programme at the University of Edinburgh "Do small molecule activators of Wnt signalling enhance differentiation and elongation of mouse intestine?"
Funder: Wellcome Trust

Abstract: Inadequate length of bowel presents a major management challenge in Paediatric Surgery. Short bowel syndrome following neonatal resection and long-gap oesophageal atresia are two examples. A method of enhancing elongation and differentiation of bowel would have significant clinical impact. Small molecules are ideal for this as they can be readily delivered to the bowel enterally or by trans-peritoneal injection. The importance of Wnt signalling in bowel growth is well established, although small molecule activators and inhibitors have not been used previously to manipulate elongation and differentiation. We plan to investigate this in a step-wise manner, starting with cell culture, followed by intestinal tissue culture and then applying the principles to a whole animal mouse model. The key goals are: 1) Cell culture: use small molecules to activate and inhibit Wnt signalling in a dissociation and reaggregation model. 2) Tissue culture: test the hypothesis that oesophageal and small bowel differentiation and elongation can be enhanced by activating Wnt signalling with small molecules in vitro. 3) Whole animal: test the hypothesis that small molecule activation of Wnt signalling aids intestinal adaptation following massive small bowel resection in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Understanding the contribution of the human microbiota to human health.
Funder: Wellcome Trust

Abstract: The human large bowel is colonized by a community of microbes, the microbiota. The major nutrients available to these organisms are dietary glycans that are not metabolized by mammalian enzymes, and host glycans presented at the surface of the intestinal epithelium The colonic microbiota makes a substantial contribution to human nutrition and health. The objective of this research programme is to understand the mechanism by which dominant members of the microbiota are adapted to metabolize the c omplex glycans presented to the large bowel. Understanding how the microbiota utilizes glycan as a carbon and energy source will facilitate our understanding of how the human diet influences the dynamics of microbiota structure. At a more global level, information on the mechanism of glycan utilization provides insight into how diet influences the capacity of the microbiota to modulate human metabolism, immunology and physiology, which has a significant impact on the health of the host. The data will also provide a functional context to the Human Microbiome Project, a multinational metagenomic sequencing programme of the human microbiota. The project will focus on enzyme function, enzyme cellular location, the extent of enzyme redundancy and resource allocation within the microbiota


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: An investigation into the epigenetic alterations in the T helper 17 pathway in the pathogenesis of Crohn's disease.
Funder: Wellcome Trust

Abstract: Crohn's disease (CD) is a disease that causes inflammation of the digestive tract. It remains incurable and an important cause of illness, with 75% patients requiring a surgical operation to remove part of their bowel within ten years of diagnosis. Over the last decade, scientists and doctors have made important advances in understanding the causes of CD. We now have much better knowledge of differences in the genetic code (made of DNA) between people who get Crohn's and those that do not. Ma ny of the key genes are essential to the proper functioning of cells in the body's immune (defence) system including special type of white blood cell called T helper 17 cells. In Edinburgh we have exciting results that suggest that a particular modification of DNA called DNA methylation has a role to play in Crohn's disease. I plan to take this research forward by investigating whether there are differences in DNA methylation in genes related to the T helper 17 cells that we already know to b e important in CD, and how this affects their function. This will be done using blood samples and samples of the intestinal lining taken from volunteers with and without Crohns disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Personalised therapy in Crohn's disease- a biomarker-stratified trail
Funder: Wellcome Trust

Abstract: Crohn's disease is a chronic, debilitating intestinal condition, which typically occurs in young adults. Once a patient is diagnosed, there is no way to know how the disease will behave over their lifetime. Some may have frequent flare-ups and require treatment that involves hospital admission, toxic drugs and even surgical removal of diseased intestine, whereas others may have very few problems For this reason, treating all patients the same way makes no sense the treatment that would be best for a patient with aggressive disease would overtreat an individual with mild disease, and vice versa. Ideally, all patients should receive the treatment that is most appropriate for them ideally at the earliest possible time. Unfortunately this personalised therapy will not be possible until doctors can reliably predict how an individual's disease is destined to behave. We have developed a specialised blood test that involves measuring genes in a subtype of white blood cell. Using this blood test, we have shown that we can identify which patients will experience aggressive disease and which will experience mild disease. We wish to use this test to personalise therapy for individuals with Crohn's disease, and assess whether this will improve their treatment and overall wellbeing.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Role of interleukin 33 in intestinal homeostasis
Funder: Wellcome Trust

Abstract: This research project will focus on the identification of the role of interleukin 33 (IL-33) in intestinal homeostasis. IL-33 belongs to the IL-1 family and has been shown to mediate both pro-inflammatory and anti-inflammatory processes depending on the disease context. Although IL-33 is produced in high amounts in the intestine little is known about its role ininflammatory bowel disease (IBD) development and progression. In this project I will use in vitro and in vivo systems, including knock-out and reporter mouse strains, in order to describe IL-33 signalling in the gut. Recent studies suggest that intestinal regulatory T cells (Tregs) express high levelsof IL-33R and that this pathway contributes to their function. I will build onthese studies to identify key downstream pathways activated by IL-33 in Treg cells that promote their function and how these are regulated by pro-inflamamtory mediators. Altogether the results of this study may lead to identification of potential novel therapeutic targets in IBD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Wellcome Trust Joint Basic and Clinical PhD Programme at the University of Birmingham: The therapeutic potential of Vascular Adhesion Protein-1 in Primary Sclerosing Cholangitis
Funder: Wellcome Trust

Abstract: Primary Sclerosing Cholangitis (PSC) is an incurable disease of the liver which causes obstruction of the bile ducts. At present, no effective treatmentexists, many patients progressing to irreversible liver scarring (cirrhosis) and liver failure. Moreover, up to 30% of patients may develop cancer of the liver, gallbladder or bile ducts. PSC is almost exclusively found in patients with inflammatory bowel disease (IBD) and despite many not having any symptoms, this group are at a greatly increased risk of developing colon cancer. The reasons why PSC is found in patients with IBD are uncertain but recent data indicates that excessive levels of a molecule called mucosal addressin cell adhesion molecule-1 (MAdCAM-1) within the liver attracts immune cells from the diseased gut in IBD. The reasons why there is excess MAdCAM-1 in the liver of PSC patients are also incompletely understood but this may be due to interactions between another molecule called vascular adhesion protein-1 (VAP-1) and a compound called methylamine (found in certain foodstuffs, wine and cigarette smoke). This proposal will use cutting edge technology to dissect the interactions between these molecules and determine whether blocking their function can slowdown or reverse parts of the disease process in PSC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Clinical PhD Programme at the University of Edinburgh: "The role of epigenetics in regulation of intestinal homeostasis and inflammation".
Funder: Wellcome Trust

Abstract: There are more bacteria in our gut than cells in our entire body. The daily challenge this presents to our immune system is substantial, with a fine balance to be struck between tolerating normal gut bacteria and defending the host from harmful micro-organisms It is the abnormal response from the host rather than the environmental trigger itself that is increasingly understood to be implicated in common conditions such as coeliac and the inflammatory bowel diseases. There is only limited scientific understanding as to why certain people are more prone to autoimmune diseases, and indeed what triggers the disease to start at all. If we could understand how alterations in our genetic makeup translate into abnormal and overactive immune response to innocuous parts of our environment we could target our treatments more effectively and indeed find new ways to treat people. Our DNA library has already been deciphered and catalogued and although this yielded great advances in our understanding doesn't explain how common some diseases we see are. We therefore propose investigating an additional layer of control, epigenetics , that can affect how our DNA is read without changing the DNA code itself. Epigenetics represents a fingerprint of information on top of our existing DNA that can be inherited and can change as a result of life experiences. Micebred to be deficient in an epigenetic regulatory pathway have changes in how their immune system functions, thus we wish to investigate how this is produced and whether it can explain why some people are more prone to autoimmune diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining the pathogenic role of cellular immune responses to alcohol dehydrogenase in severe alcohol-related liver disease.
Funder: Wellcome Trust

Abstract: There has been an exponential rise in the incidence of alcohol-related liver disease (ALD) globally and liver disease is now the fifth most common cause of death in the UK. Although the link between alcohol consumption and ALD is well established, it remains unclear why some people are more susceptible to the harmful effects of alcohol than others. Numerous studies have demonstrated a link between alcohol and an abnormal immune response. Our preliminary research shows that in some people, alc ohol acts as a trigger, causing their own immune system to attack the liver. Our study will characterise the abnormal immune response by studying a subtype of immune cells called T cells from patients with ALD. We will assess the reactivity of these cells to a protein called alcohol dehydrogenase (ADH), which is produced in the liver and is responsible for alcohol detoxification. We can then compare these results to T cells from healthy volunteers. This will allow us to assess whether people who develop ALD have abnormal immune responses to ADH due to alcohol consumption. This may identify new targets for novel treatments to modify the immune response and prevent death in this young group of patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Characterization of innate lymphoid cells in intestinal pathophysiology.
Funder: Wellcome Trust

Abstract: Inflammatory bowel disease (IBD) is a chronic disorder of the gut of unknown cause. Research suggests that an inappropriate immune response against harmless bacteria is responsible for the disease. Patients are treated with immunosuppressants, which are not always effective and have worrying side-effects. Interleukin (IL)23 is an inflammatory molecule involved in many chronic immune-pathologies. Work from the Powrie lab has identified a key role for IL23 in driving intestinal inflammation in ani mal models of colitis. IL23 expands T helper (Th)-17 lymphocytes, a population of white cells that produce IL17. IL23 can also drive colitis in mice that completely lack T lymphocytes, through its activity on innate lymphoid cells (ILC). Interestingly, we have identified IL23 responsive ILC in the human gut and found that they accumulate in Crohn's disease (CD). ILC may contribute to inflammation through the production of inflammatory molecules, but also through the interaction with tissue cells and the recruitment of other inflammatory cells. In this study, we will investigate the cross-talk between ILC and intestinal stromal cells and evaluate whether this is altered in IBD. We hypothesize that ILC may play an important amplifying role in inflammation, representing a promising therapeutic target for the treatment of patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Evaluation of bioenergetic changes In blood cells during acute pancreatitis
Funder: Wellcome Trust

Abstract: Acute pancreatitis (AP) is a potentially lethal inflammatory disease which affects approximately 50 per 100,000 individuals, costing the UK ~£1 billion per annum in patient care. Those with severe AP are more likely to develop complications and have a much higher death rate. However, existing biomarkers of AP are mostly nonspecific and unreliable, and novel approaches necessary. Mitochondrial dysfunction is a core feature of AP. Major triggers of AP, such as bile acids and alcohol metabolites, induce sustained Ca2+ levels in pancreatic acinar cells, leading to mitochondrial depolarisation, ATP depletion and necrosis. Systemic inflammation ensues and feeds back to the pancreas in a vicious cycle. Recently it has been shown that blood cell bioenergetics are altered in several diseases, assessed using the BioenergeticHealth Index (BHI), derived from mitochondrial respiratory functional analysis. Such evidence has indicated that blood cells may serve as early biomarkers of severity in inflammatory diseases. Therefore the aim of this project is to assess bioenergetic profiles of leucocytes and platelets, using a Seahorse XF24 flux analyser, from AP patients (mild/moderate/severe/critical) and normal individuals, and from murine experimental AP models (caerulein, bile acid and alcohol) with a view to possible discovery of novel biomarkers to predict severity.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Understanding sex-linked disease mechanisms in Hirschsprung's disease
Funder: Wellcome Trust

Abstract: Hirschsprung's disease (HSCR) is a congenital disorder causing obstruction of the large intestine as partial or total innervation of the gut fails to occur in development. It is one of the most common causes of neonatal intestinal obstruction with incidence rates of up to 1.4/5000 live-births in China and 1/5000 in Caucasians. The most common form of the disease, short segment HSCR (S-HSCR), comprises 80% of HSCR cases and exhibits a strong sex bias with a 5:1 male to female ratio (Badner et al., 1990; Amiel et al., 2008; Garcia-Barcelo et al., 2009). This project aims to answer the disparity in HSCR incidence between males and females, and provides a tractable model to begin to investigate and understand sex bias in numerous diseases. We will focus on a number of mouse models with S-HSCR-like phenotypes for malebias and carry out genetic crosses utilising the "four core-genotype model" (De Vries et al., 2002). The two models showing the most robust sex bias will be chosen for further study. We will then investigate whether sex bias is sex chromosome-specific or gonad/hormone-specific, identifying HSCR-associated variants, genes and/or pathways that are significant in one gender and exploring differences in their activity and function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigation of the role of hepatic stellate cell alpha-v integrins during liver regeneration using a novel conditional genetic system.
Funder: Wellcome Trust

Abstract: Liver disease represents a massive healthcare burden worldwide. In the UK, liver disease is the fifth commonest cause of death, and the number of deaths is rising yearly. Currently, the only available treatment for severe liver disease is liver transplantation. However some patients are not suitable candidates for a transplant and a severe shortage of donor organs means many patients die on the waiting list. The liver has a unique ability to regenerate and therefore therapies aimed at boosting r egeneration of a patient's own liver would be hugely beneficial. Integrins are molecules that allow cells to communicate with each other and also with areas of injury and scarring within the liver. I will investigate whether a specific integrin molecule (alpha-v) has an important role in suppressing liver regeneration in the diseased liver. To do this I will use a novel genetic strategy in mice to manipulate levels of alpha-v integrins in specific cells within the liver during the regenerativ e process. Increasing our understanding of how the liver regenerates will facilitate the design of highly specific therapies to promote liver regeneration, leading to new treatment options for patients with liver disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: From Genes to Disease: Investigating the Role Of ECM1 Variants in the Pathogenesis of Inflammatory Bowel Disease.
Funder: Wellcome Trust

Abstract: Within the past 10 years, Genome Wide Association Scanning (GWAS) has uncovered many associations between genetic variants and disease. Genetic variants involved in the physical and immunological barrier of the gut have been associated with a bowel disease called Ulcerative Colitis (UC). UC is a type of Inflammatory Bowel Disease (IBD). IBD affects 1:250 people in the UK and is a lifelong debilitating condition with no cure. It causes bowel ulceration leading to profuse diarrhoea, abdominal pain and weight loss. Sufferers may not be able to work, be reliant on strong medication, need surgery and are at higher risk of developing bowel cancer. I plan to investigate the function of a gene, called ECM1, within gut cells. ECM1 inhibits a protein called Matrix Metalloproteinase 9 (MMP9). MMP9 is important in remodelling the damaged gut wall. It works by breaking down the physical barrier of the gut. There is a delicate balance between it working enough to allow healing, or too much w hich causes further damage. My research will identify if the genetic variants in ECM1 reduce the inhibitory effect on MMP9 leading to the gut wall damage that is seen in UC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: The role and modulation of innate immune cells in Inflammatory Bowel Disease
Funder: Wellcome Trust

Abstract: The project's aim is to evaluate the role of worm products on the first line immune system. Many mouse models of disease have shown that cells called macrophages and innate lymphoid cells are very important in altering the severity of inflammatory bowel disease (a disease which causes inflammation ofthe bowel). Professors Maizels' group has shown that parasite products can dampen the immune system from overactivation in mouse models. We will use worm products to assess if these will make inflammation of the bowel better, particularly in a model that affects the macrophages and innate lymphoid cellsmentioned above (called the anti CD40 RAG-/- model). We will select the macrophages and innate lymphocyte cells out of the model and test them to see if they behave in a way that dampens inflammation. If we can demonstrate thatworm products make inflammation of the bowel better through these macrophage and innate lymphocyte cells, then we will take cells from a mouse infected with worms and put them into another mouse to see if this improves bowel inflammation in the second mouse. We aim to try to find genes that are affected by worm products, to try to find those that are protective in inflammation of the bowel (and which may be targeted by drugs to improve the disease process in the future).


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