NIHRDataInsights/HRCSData huggingface dataset:
Title: Role of iNKT cells and the lymphoid structures within visceral adipose tissue in the control of inflammation and obesity
Funder: Medical Research Council

Abstract: Adipose tissue represents an important interface between metabolism and immunity, but the molecular and cellular details of this interaction are poorly understood. Invariant Natural Killer T (iNKT) cells, a subtype of T cells enriched in adipose tissue, play a role in this interaction since extrinsic activation of these cells induces weight loss and ameliorates type 2 diabetes in mice. In addition, we recently showed that iNKT cells are also essential to the formation of Fat Associated Lymphoid Clusters (FALCs) in visceral adipose tissue during peritoneal cavity inflammation (Benezech et al, submitted). In this project, we want to determine whether the metabolic regulatory function of iNKT cells is linked to their ability to induce lymphoid cluster formation in adipose tissue. Most lymphoid clusters in the peritoneal cavity are concentrated in the omentum, but despite the omentum being known to recruit inflammatory cells into its "milky spots" (MS) during peritoneal immune challenges, the function of this organ in inflammation is poorly understood. Our preliminary experiments revealed that MS and FALCs regress during obesity. This regression is reversed by iNKT cell activation, driving a massive expansion of MS and FALCs via the recruitment of inflammatory monocytes and macrophages while their number decreases in adipose tissue. This led us to formulate the following hypothesis: MS and FALCs exert a metabolic regulatory function in the peritoneal cavity and in adipose tissue through local regulation of inflammation. Therefore, using mouse models of inflammation and obesity in relevant knockout mouse strains and omentectomised mice, we will test this hypothesis by investigating: - The roles of MS and FALCs in the regulation of peritoneal cavity inflammation. - The roles of MS and FALCS in the regulation of inflammation during obesity and iNKT cell treatment of obesity. - The role played by iNKT cells in the regulation of adipose tissue macrophages during obesity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Type 1 diabetes genetic risk and persistent beta cell enteroviral infection - a lethal combination?
Funder: Medical Research Council

Abstract: Type 1 diabetes (T1D) is an autoimmune disease which results from the selective targeting of the insulin producing beta cells in the pancreas. It is thought to arise via a complex interplay between genetic, immune and environmental factors. Over 50 different genes have been associated with the disease with >80% of these expressed by beta cells. Ingenuity pathway analyses of these has revealed a firm relationship between genetic predisposition and host anti-viral responses. There is considerable evidence implicating enteroviruses (HEVs) in the development of disease and our group has demonstrated that a low level persistent HEV infection of the beta cells, occurs in the pancreas of individuals with T1D. This correlates closely with islet hyperexpression of Class I HLA (HLA-I), which is believed to promote antigen recognition by autoreactive cells. In preliminary work, we have developed an in vitro human beta cell model of a persistent HEV infection, where low numbers of cells exhibit signs of infection, but all cells have elevated HLA-I resembling the situation in vivo. In this proposal we will target two T1D associated genes, IFIH1 and TYK2 that encode proteins involved in sensing and response to viral infections. SNPs within these genes are associated with disease in genome-wide association studies and we have selected three SNPs that cause missense mutations and lead to altered protein function/expression. This proposal will examine the hypothesis that: Defined T1D risk alleles alter beta cell responsiveness to HEV infection, promoting the establishment of a low level persistent infection which triggers specific cellular responses enhancing the likelihood of antigen recognition (elevated HLA-I) and targeting by immune cells. Uniquely, this project will examine the interplay between specific single nucleotide polymorphisms (SNPs) that influence the risk of developing T1D and an environmental component (HEV infection) implicated in promoting islet autoimmunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Inflammatory therapeutics and the role of the circadian clock
Funder: Medical Research Council

Abstract: Chronic, unresolving inflammation plays a major role in human disease, yet remains a therapeutic challenge. Key problems are lack of drug efficacy, and the significant metabolic disturbance that accompanies both the chronic disease state (notably accelerated cardiovascular risk) and long-term anti-inflammatory treatment. We have recently discovered that inflammation leads to reprogramming of the circadian clock. The mechanism involves destabilisation of the clock mechanism, as well as disturbance of the intricate cross-talk between components of the circadian clock (e.g. CRY, REVERB) and the glucocorticoid receptor. Reprogramming of the clock is likely an important feature of the inflammatory response at sites of inflammation, to loosen circadian control of inflammatory and metabolic pathways; however, progression to a systemic level can drive profound disturbance. To decipher how cellular clock dynamics and the clock:GR interface are altered by inflammation, we will use systems microscopy approaches (e.g. FCS, FCCS), functional imaging and RNA-SEQ on cell and tissue slice models. We will define molecular mechanisms and functional consequences of inflammatory reprogramming of the clock within foci of inflammation (lung and joint). To achieve this we will use novel in vivo imaging, with time series RNA-SEQ and metabolomics. This generates highly dimensional data, to which computational analyses can be used to build predictive causation models. We will extend these studies to investigate how localised sites of inflammation can disrupt the liver metabolic/circadian processes. These studies will identify pathways of destructive or emergent rhythms, which will be tested pharmacologically or genetically (using AAV delivery of CRISPR/Cas9). Finally, we will investigate how basal and disease-induced rhythmicity can be capitalised on for timed delivery of anti-inflammatory drugs, with the goal of optimizing therapeutic index.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Novel combination therapy for rheumatoid arthritis: efficacy of anti-CD3 antibody enhanced by p38 inhibitor (Work packages 1-4)
Funder: Medical Research Council

Abstract: The applicants aim to investigate the ability of OTX combined with the p38 inhibitor Losmapimod (also developed by GSK) to induce functionally suppressive T-regulatory (Treg) cell subsets in peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis (RA) patients in vitro. The applicants will also analyse the impact of this combination on cytokine release (both pro- and anti-inflammatory) by PBMC from RA patients. Different doses of OTX and Losmapimod will be tested to maximise induction of Treg whilst minimising cytokine release. These investigations will extend existing studies to include patients with psoriatic arthritis where pilot data indicates similar results as observed in RA PBMC. In addition, the effects of this combination on synovial fluid cells will be assessed.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Inflammation and Obesity
Funder: Medical Research Council

Abstract: Our group studies the complex interplay between environment, inflammation and metabolic disease. Environmental factors, such as diet and intestinal microbiota, are important modulators of physiological processes in health and disease, yet little is known about how these cues are integrated at the cellular and molecular level. We investigate the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor capable of sensing dietary components and microbial metabolites. Recent studies have highlighted the important role of AHR in the development and function of the gastrointestinal tract. Genetic deficiency in AHR is associated with compromised intestinal barrier integrity, altered microbiota composition and dysregulated host responses to pathogens and injury. Furthermore, genome-wide association studies have identified AHR as susceptibility locus in inflammatory bowel disease, highlighting the relevance of this pathway to human disease. In recent years, studies have almost exclusively focused on the role of AHR in intestinal immune cells but increasing evidence point to an important function of AHR in non-hematopoietic cells. In line with this, my lab has identified intestinal vascular endothelial cells (ECs) as being highly responsive to AHR ligands. AHR is known to be involved in vascular development with AHR deficiency linked to vascular abnormalities of the liver and heart. However, the contribution of AHR to vascular EC function in the gastrointestinal tract has not been explored. This is of particular relevance because it is now becoming increasingly recognised that vascular ECs provide a nurturing niche for tissue-resident stem cells, participate in host defence against pathogens and orchestrate tissue regeneration upon injury in various organs. The main focus of my MRC programme is to investigate how AHR modulates organ-specific functions of vascular ECs in the intestine. Our work will provide novel insights into the processes by which environmental factors modulate vascular biology at barrier surfaces and may facilitate the discovery of new therapeutic targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: OPTIMISE: Optimal preconception nutrition to offset inflammation and non-communicable disease risk in pregnant women and their children
Funder: Medical Research Council

Abstract: Chronic low-grade inflammation, characterised by persistent elevation of circulating pro-inflammatory cytokines, has been associated with the development of non-communicable diseases (NCDs). Animal studies show that both maternal under- and over-nutrition can programme the offspring for increased inflammatory load and adiposity, and cause metabolic abnormalities, and that both maternal inflammation and its impact in offspring can be reversed by nutritional interventions. Human studies have similarly shown that both maternal under- and over-nutrition are associated with offspring metabolic deficits. Some studies have shown that higher maternal inflammatory load in pregnancy is associated with greater newborn and child adiposity. We therefore hypothesise that nutritional status (dietary intake, adiposity, micronutrients) is a critical driver of inflammatory load during the preconception and pregnancy periods, which in turn, increases risk for pregnancy complications and adverse offspring outcomes, leading to increased NCD risk. The Healthy Life Trajectories Initiative programme consist of four separate but harmonised intervention studies in India, South Africa, China and Canada. The studies will test multi-faceted interventions spanning from preconception into the postnatal period, to improve maternal, infant and child health. Exposure and outcome data variables and biospecimen collection methodologies have been harmonised. In this study, we will investigate the relationship between nutrition, inflammation and risk factors for NCDs, and examine whether these associations are influenced by the intervention. We will measure selected inflammatory markers, fatty acids and micronutrients at baseline and post intervention. We will also undertake more detailed mechanistic studies to define the role of the placenta in programming of NCDs by examining inflammatory load and nutrient transport. The intervention platform will strengthen causal inference.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Regulation of inflammation during tissue repair and regeneration
Funder: Medical Research Council

Abstract: Dysregulated inflammation leading to wound retention of inflammatory cells is a major contributing factor to chronic wounds, the leading cause of non-traumatic amputations in the developed world today. In acute wounds, inflammation resolves naturally, following a switch from pro-inflammatory to anti-inflammatory gene expression in myeloid cells, although the precise regulatory mechanisms controlling this switch are unknown. We have identified a factor, Hoxa3, which is normally upregulated in wounds during this switch, but is repressed in diabetic wounds. Our recent published studies have shown enforced expression of Hoxa3 in diabetic wounds represses genes such as Traf and Irak that are required for TNF-mediated NF-kB activation. In addition, Hoxa3 upregulates Kdm3b, a histone demethylase that suppresses myeloid cell differentiation/activation. These changes are associated with a 50% decrease in the wound retention of myeloid cells and significantly improve healing. Our most recent data demonstrates that Hoxa3 protein transduction of myeloid cells can induce similar changes. Altogether, our work points to novel functions of Hox protein control of myeloid cell development and inflammation that must be pursued. The work proposed here aims to link the deregulated inflammatory response in diabetic wounds to chromatin misregulation and aberrant NF-kB modulation. Our central hypothesis is that hyperactivation of pro-inflammatory genes is due to changes in chromatin accessibility and NF-kB hyperactivation, but that these changes can be reversed by Hoxa3 gain of function via protein transduction. The work proposed here will shed light on the underlying causes of chronic inflammation in diabetic wounds and provide insight into Hox protein function in the haematopoietic system that will inform development of urgently needed therapies for chronic wounds.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Physical activity, exercise and liver disease: advancing towards an effective clinical therapy.
Funder: Department of Health (England)

Abstract: Non-alcoholic fatty liver disease is one of the commest metabolic conditions effecting people of the UK, with up to one in three of us having excess liver fat. The presence of liver is of concern as it increases the likelyhood of other conditions such as type 2 diabetes, heart disease and more serious liver conditions. Beause of its involvement in the development of these other conditions, reducing the amount of fat in the liver may be an effective way to prevent the development of these conditions. Although exercise has been shown to imporve metabolic control and hold be benefits to health and wellbeing, the effect of exercise on liver fat and liver disease is known, limiting the ability to give people with high levels of liver fat good advice. This programme of research aims to imporve knowledge about the effects of exercise upon liver fat and liver health. The programme will also develop and evaluate professional and patients development pathways for exercise behaviour in liver disease.Combined, this work programme will establish why exercise is important, what should be done and how to use exercise as a therapy in everyday clinical care.


Research activity codes: 5.7 PHYSICAL;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Pathogen sensing and response in childhood malnutrition.
Funder: Wellcome Trust

Abstract: Malnutrition is responsible for more than a third of global child deaths, because malnourished children are more susceptible to infections. While the relationship between malnutrition and infection is well recognised, the scientific principles underlying it are poorly understood. It may be that inadequate nutrition has adverse effects on the immune system (responsible for fighting infection), which we would expect to improve during therapeutic feeding. The aim of this project is to understand how the immune system works in malnourished children. By conducting a range of laboratory tests of immune function in malnourished children sequentially, as they recover with improved nutrition, we will identify which parts of the immune system are affected and how long they take to improve. Then we will follow groups of children with combinations of malnutrition and infection, to see whether the combination of these conditions worsens immune function even more. We believe that by better und erstanding effects of malnutrition on the immune system we will be able to tailor management of malnourished children towards improving their immune function quickly. We hope that the results will be able to be used in clinical trials of new therapeutic approaches to the management of this most deadly condition.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Analysis of the metabolic profiles of differentiated human macrophages and their influence on chronic inflammation and infection
Funder: Wellcome Trust

Abstract: 1. Determine the characteristic metabolic profiles of differentiated M1 and M2 macrophages 2. Investigate the effects of hypoxia on differentiation to these characteristic profiles and integrate this with understanding of cellular activation, cytokine production and gene transcription. 3. Investigate whether other potential environmental factors (including but not limited to intracellular pathogens) modify the host cell metabolism 4. Determine the effects of intracellular pathogens on host cellular differentiation and cytokine production in response to external stimulation


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: Statistical techniques for colocalisation analysis to understand the related genetic etiology of autoimmune diseases
Funder: Wellcome Trust

Abstract: Colocalisation analysis tests genetic data for consistency of the existence ofcommon causal variants between complex traits. The co-morbidity often seen between autoimmune diseases is highly suggestive of shared causal variants; researchers have also identified many loci associated with several diseases. However, demonstrating that a variant is associated with two traits is not sufficient to show that it is causal for both; instead this may be due to distinct variants in linkage disequilibrium. Existing colocalisation methods assume independence of datasets. This is a legitimate in the case, for example, of comparing case control against eQTL. However, the commondesign for analysing two disease traits is that of a shared control. My PhD will focus upon the development and extension of colocalisation algorithms. I will extend existing software and apply the extended methods to a range of datasets chosen to advance our understanding of the shared and distinct genetic etiology of autoimmune diseases, and type i diabetes in particular. I will also look at other potential mediatingtraits, such as gene expression, which may reveal causal genes and the immune cell subsets in which they act for regions whose in influence on T1D acts through regulatory variants.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: MICA: A UK-wide networking partnership to facilitate collaborative research in the idiopathic inflammatory myopathies
Funder: Medical Research Council

Abstract: The term myositis refers to a group of rare autoimmune diseases affecting about 10,000 UK patients, the idiopathic inflammatory myopathies (IIM), which cause muscle weakness and disability. It is imperative to bring together IIM expertise and knowledge in the UK to improve infrastructure and coordinate research, clinical trial and training activities. To address this, a clinical and scientific network, UKMYONET, was established by the applicants. Funding for laboratory-based research work on samples recruited through UKMYONET has been available via an Arthritis Research UK programme grant, but no funding supports UKMYONET administrative costs. Similarly, there is no current professional funding to support training opportunities or UKMYONET meetings. The partnership grant would provide funding otherwise not available by other funding streams. The funds requested will facilitate coordinated UK-wide research activities including genetics, serology, and fundamental cellular mechanisms, and align parallel efforts for adults and children with IIM. Research activities will use datasets including ongoing collection of a core clinical dataset, establishment of a UK-wide adult IIM prospective cohort study, a national treatment outcomes registry to assess the safety and efficacy of novel therapies and establishment of a national myositis biobank. The resource will allow implementation of international research activities to be conducted using UK-based resources and expertise, including validation of new classification criteria and definitions of disease improvement/worsening/remission, and consensus on diagnostic and treatment approaches. Training workshops and visits will allow health care professionals to gain disease-specific experience. Overall, a more coordinated, collaborative approach and sharing of expertise for IIM research and patient care is anticipated to improve translation of existing/emerging research outputs and knowledge into clinical practice.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL