NIHRDataInsights/HRCSData huggingface dataset:
Title: Predicting urban food insecurity under climate change in Brazilian Amazonia
Funder: Economic and Social Research Council

Abstract: The ultimate goal of climate policy is to mitigate climate change by reducing greenhouse gas emissions. However, this is a strategy with decadal or centurial timescales. An equally important and more urgent concern is to reduce the impacts of climate change by improving the adaptive capacity of poor, marginalized populations to severe weather events such as droughts and floods. Extreme events such as floods and droughts cause significant economic losses, and threaten human health and food security. droughts probably have the greatest negative impacts in regions such as the Amazon, where river transport is the main way of distributing food. For example, Amazon droughts in 2005 and 2010 disrupted food distribution and led to dozens of deaths from malnutrition and declarations of state of emergency. Increased journey times and transport problems leads to higher food prices. When food prices are high, poorest families suffer most and lack access to adequate food and nutrition. The danger that droughts pose to food security in these regions will increase in the future because of climate change causing reduced rainfall, which leads to lower river levels. This project will develop a computer-based tool for predicting where and when food security of city-dwellers will be threatened by droughts, because of higher food prices. The tool will be based on data that we collect in small cities in the Amazon, including prices of important foods (meat and rice, for example). We will also use a series of questions to establish whether urban families have sufficient access to nutritious and affordable food. We will combine this information with information on river levels and poverty distribution across the whole Amazon (collected by the Brazilian government) and analyze data using statistical techniques normally used to predict disease outbreaks. The outcome of this analysis will be a tool that can generate maps to show the level of Food Security Risk for each of the hundreds of municipalities in the Amazon. This will help the Brazilian government to be strategic and invest their resources in the cities that are predicted to have most people suffering from malnutrition during droughts.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: ORAL AND GASTROINTESTINAL
Title: A Pharmacokinetic Study Of The Combined Use Of Recombinant Human GH And IGF-1 In Children With Crohn’s Disease
Funder: Chief Scientist Office (Scotland)

Abstract: Optimal growth and anabolic effects of GH depend on systemic and local effects of GH and IGF-1. Recent studies by our group show a clear benefit of rhGH therapy on growth in children with IBD but this is accompanied by an impairment of insulin sensitivity. Addition of rhIGF-I might reverse this trend whilst improving growth outcome. It is anticipated that a clinical trial of combined administration would form the basis of a larger, multicentre clinical trial that would eventually lead to a licence for the use of combined therapy in children with growth retardation and chronic inflammatory disease. This proposal discusses the rationale for this programme and provides a detailed work plan for initial studies that will investigate the pharmacokinetic profile of combined administration of rhGH and rhIGF1. Part funding has already been secured from the company which will supply the drugs. There is a need to support the CRF support costs for this study.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigation of vimentin as a regulator of NOD2 responsiveness to adherent-invasive E. coli in the pathogenesis of Crohn’s disease
Funder: Chief Scientist Office (Scotland)

Abstract: Recent genetic discoveries, principally the identification of NOD2 and ATG16L1 as susceptibility loci, strongly implicate a dysregulated host response to enteric bacteria in the pathogenesis of Crohn’s disease (CD). We have identified the cytoskeletal protein vimentin as potential regulator of NOD2-induced autophagosome formation/distribution in vitro and demonstrated that vimentin acts as a receptor for E.coli with adherent-invasive phenotypes (AIEC). We now propose to characterise vimentin expression in ileal CD, explore the influence of vimentin on the invasiveness of a panel of CD-associated AIEC, identify important virulence factors, and define the regulatory pathway involving NOD2, vimentin and ATG16L1, a control point of bacterial autophagy. Finally, we shall extend our intriguing preliminary data which suggest that WFA Withaferin-A (WFA), a steroidal lactone which specifically binds to and inhibits vimentin may be of therapeutic value.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Tissue Engineering of 3D Human Hepatic Organotypic Model Using Novel Cell, Biomatrix and Bioreactor Enabling Technologies for Pharmaceutical Applications
Funder: Chief Scientist Office (Scotland)

Abstract: Hepatocytes cultured In conventional 2D static culture rapidly lose polarity and differentiated function. Due to limited availability of normal human liver tissue, standard in vitro pharmaceutical models for drug metabolism/ toxicity assays use 2D monocultures of rodent primary hepatocytes or human immortalized cell lines, which are not representative of normal liver tissue. In order to reduce the high cost and attrition rates of drug development, our aim is to develop 3D hepatic organotypic co-cultures as a powerful new in vitro tool for modelling human liver for downstream pharmaceutical drug metabolism/ toxicology applications. We will use established tissue engineering principles coupled with integration of enabling technologies developed by our consortium, including: i) Stable/ functional human HepaRG hepatocytes; ii) Appropriate biocompatible, 'tunable' biomatrix with liver-like gel modulus (defined by AFM); iii) Construct vascularization via hepatic-endothelial cell co-cultures; and iv) Bioreactors that provide a defined physicochemical/physiological microenvironment to promote 3D organotypic tissue.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Monocyte-macrophage activation in acute liver failure: a mechanism to develop the systemic inflammatory response syndrome
Funder: Chief Scientist Office (Scotland)

Abstract: Acute liver failure (ALF) is a devastating clinical condition requiring liver transplantation or expensive intensive care. We and others have observed the outcome of these patients is not related to the massive live cell necrosis in ALF, but is predicted by the systemic inflammatory response syndrome (SIRS) that develops. We believe that SIRS is due to an aberrant response of the patient’s monocyte-macrophage cell lineage to liver cell death and is different from patients that never develop SIRS. Our aim is to define the phenotypic differences (cell surface marker expression, phagocytosis and cytokine production) in these cell types in patients with and without SIRS and those who subsequently develop SIRS during ALF. These data would produce better biomarkers of ALF outcome, direct future research into novel therapies and using ALF as a paradigm of SIRS following tissue injury have wide-reaching clinical application in other fields, such as burns and trauma.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: The Paediatric-Onset Inflammatory Bowel Disease Cohort and Treatment Study (PICTS)
Funder: Medical Research Council

Abstract: This project will focus on the consolidation and expansion of a proven, scientifically important cohort of Scottish patients with childhood-onset inflammatory bowel disease (IBD). Scottish families with IBD strongly support this research, with over 450 cases in the cohort to date, all with comprehensive phenotypic description and extensive genetic analysis. Expansion will allow a near-complete ascertainment of cases of IBD diagnosed 16 years of age in Scotland, provide a complete geographical spread throughout Scotland, and expand numbers in the rarer subtypes of IBD. Follow-up will allow characterisation of disease progression, natural history, responsiveness to therapy, and of pathogenetic factors. SUCCESS OF COHORT TO DATE: ? Enrollment of over 450 cases of childhood-onset IBD in Scotland ? Built on epidemiological study of this population for more than 4 decades and genetic studies for the last 8 years ? Very high acceptance by children and families ( 99% recruitment in SE Scotland) ? Rigorous and extensive phenotypic characterisation of cohort ? Demonstration of extensive disease at childhood diagnosis and rapid progression in extent and disease behaviour ? Demonstration of geographical and socio-economic variance in disease prevalence within Scotland ? High impact publications on paediatric phenotype and genotype-phenotype relationships ? Research group at international forefront of phenotypic and genotypic analysis of childhood-onset IBD ? Close links with international groups with similar childhood-onset IBD cohorts, and also more widely in adult Gastroenterology ? Development of paediatric clinician scientists with skills in translation medicine ? 500,000 SNP genetic profiling of 410 Scottish children with IBD available shortly EXPECTED RESULTS OF EXPANSION OF THIS COHORT: ? Increase in cohort size to 1000 by 3 year study end ? Completion of full geographical ascertainment will permit further study of epidemiological and environmental risk factors for IBD ? Characterisation of pathogenetic factors by parallel epidemiological, genetic, serological, and proteomic studies ? Fuller characterisation of disease progression and natural history, especially in rarer sub-types of IBD ? Intervention studies ? pilot feasibility RCT and full RCT for both induction of remission and maintenance of remission in childhood-onset IBD ? Characterisation of responsiveness to therapy ? Determination of safety of exposure to new biological therapies in IBD


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining the cellular and molecular pathogenesis of ulcerative colitis
Funder: Medical Research Council

Abstract: Ulcerative Colitis (UC) is an inflammatory bowel disease of unknown aetiology and rapidly rising incidence that causes significant morbidity and mortality and represents a significant unmet healthcare need. We have recently developed a novel model of UC (TRUC=T-bet, RAG, Ulcerative Colitis) that begins to explain many aspects of this disease at a cellular and molecular level (Cell 2007; 131, 33-45). This model has been highlighted as revealing fundamental insight into disease pathogenesis (Cell 2007; 131, 15-17) and having particular relevance for translation (NEJM 2008; 358, 528-530). The absence of the transcription factor T-bet in the innate immune system causes a spontaneous, transmissible and fully penetrant colitis that is a phenocopy of human UC. The severity of this disease can be modulated by adoptive transfer of regulatory T cells (Tregs), antibody blockade of TNF-alpha and is also critically dependent on the gut microflora. Based on a substantial body of new data, we will define our model in further detail and provide the translational platform for novel therapeutic modalities for human UC. We will: 1. Determine the cellular and molecular mechanisms of disease pathogenesis. i. As natural killer (NK) cells are hyperactivated in the TRUC mouse, these cells are probably important determinants of colitis. We will address this by antibody-mediated and genetic deletion of T-bet and NK cells in TRUC mice. ii. At the molecular level, the defect appears to map to transcriptional repression at the TNF-alpha promoter by T-bet in colonic dendritic cells (DCs). We will test if DCs are critical for the pathogenesis of colitis by selective depletion of DCs utilizing the CD11c-DTR/GFP and T-betfl/fl x CD11c-Cre mouse. iii. We have found that colonic epithelial apoptosis is the earliest histological event observed in the TRUC mouse. By crossing the TRUC model with the Lgr5 reporter mouse, we will be able to follow stem cell kinetics as colitis evolves to determine the role of the colonic epithelial stem cell in UC pathogenesis. 2. Elucidate the pathways that control colitis at a cellular, therapeutic biological and microbiological level. i. We will investigate whether adoptively transferred Tregs directly control DC cytokine production. ii. We will ascertain the most effective biological therapy for colitis. iii. We will determine the cytokines involved in transmitted colitis and the response to biological therapy. By validating these findings in parallel with human studies, we will translate our findings into real change in the management of human UC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Autoantigen-specific regulatory T-cells: a new tool for tolerance induction in autoimmune hepatitis
Funder: Medical Research Council

Abstract: Autoimmune hepatitis (AIH) is a severe liver disorder requiring life-long immuno-suppressive treatment, which may cause serious side-effects and despite which transplant-requiring end-stage liver disease may occur. Due to its frequently acute presentation, AIH offers the unique opportunity to follow the evolution of liver damage from the very onset to cirrhosis and/or transplantation. The involvement of autoreactive B, CD4 and CD8 T-cells in AIH is well documented with the three arms of the immune response converging on discrete antigenic regions. We have provided evidence that this multipronged immune attack is associated to a numerical and functional impairment of regulatory CD4+CD25+ T-cells (T-regs), a cell subset central to immune-tolerance. Though functionally inefficient, T-regs from patients with AIH can expand in number and augment their suppressor function when exposed to high dose interleukin-2 and anti-CD3/anti-CD28 T-cell expander. T-regs expanded for up to 4 weeks maintain phenotypic characteristics of the original T-regs, such as the forkhead-winged helix transcription factor BOX P3 (FOXP3) and suppress much more efficiently than freshly isolated T-regs. Using the same approach I also succeeded in obtaining T-regs from CD4+CD25- T-cells, a subset mainly composed of effectors, but also including a proportion of cells with regulatory potential. T-reg ability to expand and to suppress has been mainly investigated in a non-antigen-specific setting. There is evidence, and I have supporting preliminary data, that antigen-specific suppress more efficiently than non-antigen-specific T-regs. AIH provides an ideal model for the generation and potential therapeutic use of antigen-specific T-regs, as the autoantigenic targets are known. Using different approaches I propose to generate and expand antigen-specific T-regs from CD4+CD25+ and CD4+CD25- T-cells. The goal is to generate and expand cells with therapeutic potential due to their ability of delivering suppressive signals to effectors of the autoimmune attack. I will investigate whether T-regs maintain their functional commitment over time. To this end I will focus on a subset of T-regs expressing the ecto-enzyme CD39, a molecule recently proposed as marker of T-reg ‘stability‘. As a first step towards clinical application, I will test the safety of patients-derived antigen-specific T-regs following injection into NOD/SCID/gamma mice and I will evaluate their survival in vivo. If successful, this study would provide proof-of-principle for the feasibility of tolerance induction not only in AIH but also in other autoimmune disorders, collectively representing 5% of the human disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Identifying genetic susceptibility factors for paracetamol-induced hepatotoxicity
Funder: Medical Research Council

Abstract: Aims & Objectives To characterise genetic loci and identify candidate genes responsible for the heterogeneous response to acetaminophen (Paracetamol/APAP) and the development of APAP-induced acute liver failure. Design I will exploit both naturally occurring and induced genetic variability in mouse models to identify novel genes that influence APAP susceptibility. The primary focus of my studies will be the characterisation of novel mouse models exhibiting heritable APAP sensitivity generated by an existing ENU mutagenesis programme. To complement these studies I will also complete an inbred strain survey for APAP sensitivity which will inform strain selection for a QTL mapping experiment and allow in-silico studies using established polymorphic SNP resources. Methodology Our research group is undertaking a phenotype-driven ENU-mutagenesis screen for APAP-toxicity, so far nine mutants with heritable APAP sensitivity have been identified. During my Academic Clinical Fellowship I conducted a pilot QTL mapping project that identified an association between APAP-sensitivity and a locus on murine Chromosome 18. I will investigate genetic susceptibility to APAP-hepatotoxicity using a number of genetic techniques. I will select two of the most promising ENU mutant lines to take forward for further study. Using established breeding strategies and SNP genotyping I will determine the genomic region associated with the observed phenotype and identify the causative mutation by sequencing candidate genes. Having identified the mutation I will then proceed to explore how it perturbs gene function and promotes APAP sensitivity through 1H-MRS and LC-MS metabonomic studies. Parallel to these investigations, I will survey APAP sensitivity in a panel of 12 inbred mouse strains and use established SNP maps in silico to identify genetic loci associated with susceptibility. Building on the pilot study I conducted and information derived from the inbred strain panel I plan to conduct a further QTL mapping experiment with mouse strains showing extremes of response to APAP. Scientific and medical opportunities Recent evidence demonstrates mild hepatotoxicity in patients taking therapeutic doses of APAP. As well as providing new insights into severe APAP toxicity, this project will further our understanding of the genetic causes of this phenomenon. The knowledge generated may lead to novel therapies for acute liver failure and improved recognition of patients experiencing derangement in their liver function due to use of this common analgesic.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Characterising IBS subtypes and their response to Stress using MRI
Funder: Medical Research Council

Abstract: Irritable Bowel Syndrome (IBS), characterised by recurrent abdominal pain and erratic bowel habits, is the commonest cause of outpatient consultation in gastroenterology. Over 50% of IBS patients are clinically anxious, 65% believe their typically erratic symptoms are linked to stress and many relate disease onset to a stressful event. However there are a number of key problems in the management of IBS. First IBS patients are heterogeneous, with different responses to therapy and most likely different aetiologies . Secondly there is no objective biomarker for IBS or its subtypes. We intend to develop objective MRI tests for IBS to address both these problems Animal studies have shown that stress acting through Corticotrophin releasing factor (CRF) stimulates increased small intestinal and colonic motility via activation of mast cells, whose numbers are known to be increased in IBS. We have used novel magnetic resonance imaging (MRI) techniques to show that IBS patients with diarrhoea (IBS-D) have constricted small bowels with rapid transit. We have also shown that CRF reduces small bowel water content in healthy subjects by 36% and previous small studies have shown exaggerated stimulation of motility of small and large bowel segments by CRF in IBS. We have previously found the constriction of the small bowel in IBS-D was correlated with anxiety which is equally common in all subtypes of IBS including those with constipation or mixed bowel habit. We hypothesise that stress will cause these subtypes to also have reduced small bowel water content and that the different bowel habit will depend on differences in colonic responsiveness which we will assess using our novel MRI parameters. We will optimize our imaging techniques to develop an efficient economical protocol to allow us to non-invasively define abnormalities of small bowel and colonic water content and transit in patients with various subtypes of IBS. Simultaneously we will assess mast cell numbers and their release of mediators in biopsies from the IBS patient‘s colonic mucosa. We will also assess psychological stress using psychometric questionnaires to test the hypothesis that the MRI assessments of the small and large bowel in IBS will show a link with stress. Our studies will provide a better understanding of the effect of stress on the intestine in IBS and provide a potential biomarker for characterizing individual patients and predicting their response to treatments


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Exome sequencing and mutation identification in familial coeliac disease
Funder: Medical Research Council

Abstract: Coeliac disease is highly heritable, however at most 50% of this heritability is explained by HLA-DQ and new risk variants from genome wide association studies. We hypothesise that rare heritable genetic mutations (protein coding changes) of relatively large effect size (allelic odds ratios ~ 2 - 5) account for a substantial proportion of the remaining heritability in coeliac disease. We propose to use whole exome resequencing to identify mutations in 50 selected very large multiply affected families. We will resequence exons of all protein coding genes in, where possible, three distantly related individuals per family (each pair at least 1st cousin or more distant). We have already identified and collected DNA and phenotypes on over 100 families with at least 5 affected coeliac individuals and will select 50 of the most informative families to exome resequence 3 distantly related affecteds per family.. Importantly, the use of relatively inexpensive genome wide SNP chips in large pedigrees allows us to accurately identify extended genomic segments shared between distantly related affecteds that are likely to be the regions containing mutations. We will subsequently genotype a set of candidate mutations per family in all affected and unaffected individuals to confirm segregation with affection status. We will then perform deep resequencing of the 4 most interesting genes containing mutations segregating with disease in ~1000 samples, to obtain the full mutation spectrum in coeliac disease. We will proceed to genotype these mutations; promising mutations from exome resequencing in sporadic extreme-phenotype coeliac disease (a separate Coeliac UK funded project); and other promising mutations from familial resequencing in our entire collection of over 8000 cases and 8000 controls. Identifying rare high effect size mutations in coeliac disease will give us direct leads into the causation of disease, and identify novel therapeutic targets. Rare mutations often have readily predicatable pathological consequences, e.g. stop mutations or deleted exons. Follow on studies will investigate the effects of these mutations on biological function. The study will likely also generate methodological advances relevant to other diseases with complex inheritance.


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