NIHRDataInsights/HRCSData huggingface dataset:
Title: MRC Centre for Transplantation
Funder: Medical Research Council

Abstract: In 2007, the Centre set out to convert its extensive knowledge of inflammation, immunity and tolerance into new treatment, diagnostic and prognostic technologies for the benefit of patients. Our priorities were to overcome the initial barriers to transplantation presented by the immune system and to induce tolerance in patients with guidance from immune prediction and monitoring, so reducing some of the major limitations of modern transplantation. To do this, we created links with protein and cell therapeutics, imaging sciences and genetics, and between clinical specialities responsible for the treatment of patients with diabetes, liver, kidney, bone marrow and dental diseases. As a result, the first membrane-targeted therapeutic regulators are about to enter a multicentre efficacy trial; the cell therapy strategy has progressed to become part of several investigational protocols designed to induce tolerance; markers of tolerance are undergoing extensive evaluation in man; and new imaging ligands that detect activated complement fragments and migratory T cells have emerged. A teaching framework built around these goals is equipping trainees to engage in multidisciplinary research. A programme of patient and public involvement promotes awareness of the importance of science in transplant medicine and ensures we are responsive to their expectations. Our plan is to regroup the expanded number of basic and clinical research programmes into fewer themes which reflect areas of strategic value. This includes islet and hepatocyte transplantation, where inadequate long-term outcomes are likely to benefit from the specific expertise of the Centre. In support, an expanded training scheme will develop leadership skills in the distinct areas defined by the new themes, i.e. protein and cell engineering, immune monitoring, imaging and informatics. A parallel theme to improve methods of health economic assessment for early research is designed to support these goals.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: The TWO Study: A Phase II trial of regulatory T cells in renal transplantation - can we achieve sirolimus monotherapy?
Funder: Medical Research Council

Abstract: Transplantation is the most effective treatment for end-stage kidney disease. Yet despite major improvements in immunosuppression, long-term transplant survival rates remain poor. Excellent short-term survival rates are achievable with tacrolimus and mycophenolate mofetil (MMF) combination therapy, but this is associated with side-effects that include nephrotoxicity and neoplasia. Reducing immunosuppression is possible by incorporating alemtuzumab induction with early conversion from tacrolimus to sirolimus and combination therapy with MMF. We are currently exploring the potential benefit of combined sirolimus and MMF in the multi-centre Phase IV 3C Trial. In an earlier Phase II study we explored immunosuppression reduction through MMF cessation and sirolimus monotherapy but this strategy was abandoned due to a high rate of acute rejection when MMF was discontinued. Nevertheless, if achievable, sirolimus monotherapy would support enhanced renal function and fewer side-effects. Regulatory T cell (Treg) therapy has shown promise in early clinical studies, and may promote conditions that allow immunosuppression reduction. We are currently leading a Phase I study in renal transplant recipients to assess the feasibility and safety of Treg therapy (the ONE Study). This dose escalation trial has demonstrated that production of clinical-grade Treg is feasible and that there are no adverse reactions following administration. There is an attractive argument for combining Treg with sirolimus monotherapy, since sirolimus may facilitate the survival of Tregs. The study proposed is a 5-year single-arm Phase II immunosuppression minimisation trial in deceased and living donor renal transplant recipients, assessing the ability to achieve monotherapy with sirolimus with the use of adjuvant Treg therapy. The primary outcome will be the incidence of acute rejection episodes at 12 months post-transplantation. Results will be compared with matched controls from the 3C Trial.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: Reducing the risk of post-hepatectomy liver failure using a novel MRI method to predict post-operative function.
Funder: Medical Research Council

Abstract: STUDY DESIGN Prospective, single-center observational cohort study recruiting HCC patients considered for curative liver resection, and patients with colorectal liver metastases (CRLM) considered for major resection. They will be divided into 3 treatment groups: surgery (n=184), PVE followed by surgery (n=15), no surgery (n=47). DCE-MRI will be added to the preoperative MRI, as well as an ICG test on the same day. The PVE group will have an additional MRI after PVE. Patients will be followed up until 90 days after surgery. DCE-MRI data will not be shared with the clinical care team and processed with blinding to patient history. The processing protocol will follow the same steps as in the pilot study, but a more practical semi-automated workflow will be created for this study. This will include automated segmentation facilitated by image registration for motion correction, and development of an open-access software plugin. DATA ANALYSIS Objective 1. The accuracy of DCE-MRI will be determined by comparing total liver function against the reference method ICG, and the results will inform statistical analysis. Functional bias of the FLR will be calculated as in the pilot study (figure 2), and the association with PHLF will be tested by univariable logistic regression analysis. A multivariable analysis will be performed to identify associations with other predictors. Objective 2. Models will be developed to predict PHLF using cross-validation, including those based on standard logistic regression and generalised additive models to accommodate potential for nonlinearity and interactions. The model will be used to design (1) a risk assessment strategy that maximises PHLF reduction using a minimal panel of biomarkers; (2) a clinical trial. Objective 3. In group B, function, volume and perfusion of the FLR, occluded segments and the tumor will be determined as a function of time. It will be tested whether temporal patterns are predictive of outcome.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: MECNUT: Impact of dietary exposure to emulsifiers on the intestinal mucosa - implications for inflammatory bowel disease and metabolic syndrome
Funder: Medical Research Council

Abstract: We have shown that very low concentrations of food emulsifier Polysorbate 80 cause bacterial translocation across human ileal epithelium and that this occurs transcellularly across both M (microfold) cells and non-M epithelial cells. Subsequent mouse studies show that dietary polysorbate 80 induces bacterial translocation, intestinal inflammation and metabolic syndrome. This raises the possibility that dietary emulsifiers might be factors in conditions such as coronary artery disease, type 2 diabetes and Crohn's disease. It is not known whether this effect applies equally to all emulsifiers/detergents; e.g. including the natural emulsifier lecithin or possibly even conjugated bile acids present in the distal terminal ileum where bacteria may have refluxed through the ileo-caecal valve. The proposed studies will investigate effects of a wide range of permitted food emulsifiers, low concentrations of dishwashing detergent (sodium laureth sulphate), conjugated bile acids on bacterial translocation in cell monolayers and in murine and human intestinal organoids (small intestine and colon). At least 5 emulsifiers will then be assessed as dietary additives in mice with circulating bacterial DNA, intestinal inflammation and metabolic syndrome (body weight/blood glucose) as endpoints. An established collaboration (Linkoping, Sweden) will assess the impacts of at least 3 emulsifiers on bacterial (E. coli) translocation across cultured human terminal ileum explants. Co-investigators at Aberdeen University will examine dietary lecithin supplementation in a 6-week cross over study in 25 human volunteers with circulating bacterial DNA, fasting blood glucose, faecal calprotectin and balance and activity of the gut microbial community as endpoints. These studies will clarify the health implications of exposure to these various dietary and washing detergent/emulsifiers and better inform the public and the food industry regarding healthy dietary and food processing practices.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: Investigating hormone secretion in response to altered nutrient delivery to the distal gut
Funder: Wellcome Trust

Abstract: After a meal, enteroendocrine cells (EECs) along the gut sense nutrients. One type of EEC, the L-cell, responds by releasing hormones like GLP-1 which primes the body to deal with increased blood sugar by instructing the pancreas to release insulin. Gastric-bypass surgery leads to weight loss and in patients suffering from type 2 diabetes can also reverse this disease state, with increased GLP-1 credited in part for this. Blocking SGLT1 (a transporter needed for glucose uptake from intestine to bloodstream), also improves blood sugar control through increased GLP-1 secretion. How gastric-bypass or blocking SGLT1 affect GLP-1 secretion is not fully understood but we believe a possible explanation in both cases is that nutrients are present or broken further down the gut than in normal physiology and that these breakdown products are promoting GLP-1 release from resident L-cells in the distal gut. We will study the gut contents of mice after SGLT1 inhibition or gastric-bypass surgery compared to normal mice after a meal. Any candidate break-down products will then be tested on isolated L-cells to measure GLP-1 response. Mimicking GLP-1’s effects forms the basis for many anti-diabetic drugs and we therefore hope that our study may lead to new treatment opportunities.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: University of Aberdeen and Elasmogen Limited
Funder: Innovate UK

Abstract: To develop the knowledge and capability to design, construct and test new and efficacious bi-specific drugs for liver disease; a 'silent-epidemic' driven by growing levels of obesity and diabetes and where no effective drugs currently exists.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: Nutrition, Diet and Lifestyle (including obesity)
Funder: Department of Health and Social Care

Abstract: We aim to translate novel findings of causal effects of nutrition, sedentary behaviour and lifestyle on outcomes, drawn from population clinical and experimental studies, to develop interventions to improve the health of children and adults with conditions related to (or compromised by) poor or sub-optimal nutrition or inactivity. Short term S1. Identify, using large-scale molecular and genomic approaches, nutritional modifications for people with prostate and head and neck cancer (workstream 1 (WS1)). S2. Develop and test interventions to reduce energy intake and sedentary time (WS2). S3. Work with families and industry partners to identify nutritional biomarkers of disease severity and nutritional and device interventions to improve outcome in children with chronic disease (WS3). S4. Identify nutritional interventions in the peri-treatment period to improve outcomes of major hospital treatment (WS4). Medium term M1. Conduct feasibility studies to: a) improve metabolic status of men with prostate cancer (WS1); b) improve food choice and reduce energy intake in people with type 2 diabetes (WS2); c) test novel interventions and medical devices in children with chronic disease (WS3); and d) improve outcomes of surgery or chemotherapy (WS4). M2. Develop behavioural interventions (including use of wearable technologies) in a) secondary prevention of oral and laryngeal dysplasia (WS1); b) weight management (WS2); and c) children with diabetes (WS3). Long-term L1. Refine and finalise interventions so they are ready for definitive testing in well-designed adequately-powered randomized trials. L2. Develop protocols and applications to run phase III trials and validate biomarker findings in other groups.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;CANCER AND NEOPLASMS
Title: Co-production of 'Health Connections' - a community-based diet, physical activity, and healthy weight intervention for UK Black and Asian adults
Funder: Medical Research Council

Abstract: Current health communication and behaviour change programmes do not support UK Black and Asian populations in making healthier dietary and physical activity (PA) choices, and maintaining a healthier weight. We aim to co-produce 'Health Connections' - an ambitious new intervention tailored to the needs of Black Caribbean, Black African and South Asian men and women, embedded in communities and delivered by peer-educators supported by health professionals. Components will include a culturally sensitive social marketing campaign; equitable, flexible opportunities and psychosocial support to promote favourable diet and PA choices, and healthy weight; and cultural competency training to enhance partnerships between health professionals and peer-educators. The project is underpinned by a systems perspective, positing collective efficacy within communities, behaviour change theory, and co-production. Semi-structured interviews will be conducted with men and women from diverse South Asian ethnic groups to understand their experiences, perspectives and intervention needs, adding to our existing data from Black ethnic groups. We will synthesise the data, literature, existing intervention resources and local practice, and develop the theoretical framework to co-develop intervention goals, programme theory, and a draft logic model of change. A theorised list of potential intervention components, session content, and mode/s of delivery will be explored in a Delphi exercise and workshop to achieve consensus on the intervention format; and we will develop prototype materials, and a formal implementation plan. An intervention manual and a plan for testing and evaluating feasibility and acceptability, and process, outcome, and cost effectiveness within a pilot trial, will be co-designed. Dissemination suitable for a range of stakeholders and audiences will include publications, presentations, and an infographic.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE
Title: Exploring genetic risk profiles for diabetic nephropathy by extending meta-analyses of genome-wide association studies
Funder: Diabetes UK

Abstract: Aim: To improve our knowledge and understanding of biological pathways and genetic risk factors that influence diabetic nephropathy. All recruited individuals are White, diagnosed with type 1 diabetes <35 years of age with diabetic nephropathy (macroalbuminuria or end-stage kidney failure, cases) or without evidence of renal disease (controls). Recent research evaluating ~2.4 million SNPs in >6,000 individuals has identified top-ranked makers associated with diabetic nephropathy, in particular for individuals undergoing renal replacement therapy (P=4.8 x 10-09). We propose replicating these top-ranked hits in 3,000 additional individuals with similar phenotypic criteria to those recruited to the original study. We also plan to compare our results for end stage kidney failure to cleaned data obtained from the Wellcome Trust Case Control Consortium 3 Renal Transplant Dysfunction Study. This represents a unique opportunity to compare two large UK-based datasets for kidney disease. Next generation sequencing will be conducted for five prioritised regions, extensive bioinformatics performed and further SNPs genotyped by Sequenom and TaqMan. Complementary to the described research, additional work analysing copy number variation and next generation sequence data from the mitochondrial genome will be conducted. This project will generate considerable novel information that will be made available to the wider research community.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: The effect of TGF-beta on connexin-mediated signalling: a role in diabetic nephropathy.
Funder: Diabetes UK

Abstract: Diabetic nephropathy (DN) is the single commonest cause of entry into the renal replacement therapy programme and represents the leading cause of end-stage renal failure in both Type I & Type II diabetes. Almost one third of all patients with diabetes progressively develop DN within 10-to-30 years of the onset of disease where tubulointerstitial fibrosis represents the final common cellular pathway. New fibroblasts are derived mainly through epithelial-mesenchymal cell transition, and transforming growth factor beta (TGF-beta) represents the key fibrogenic mediator of these glucose-evoked changes. Tubular epithelial cells normally form a highly coupled epithelial sheet held together by the adhesion molecule epithelial (E)-cadherin (ECAD) that allows for inter-cellular communication through connexin (Cx)-mediated gap-junctions (GJ). However, nearly nothing is known of the physiological role of Cxs in the tubular system. There is obvious crosstalk between Cx and adherens junction proteins, and we suspect that a loss of ECAD expression represents the beginning of a series of events culminating in the dissociation of cells within the epithelial sheet and loss of connexin (Cx)-mediated cell-communication in EMT. The proposed investigation will utilise a number of sophisticated molecular and single-cell technologies to fully characterise Cx-expression/function in orchestrating intercellular communication in the proximal tubule. Normal activity will be compared to that observed in response to TGFbeta to understand how this pro-fibrogenic factor disrupts adhesion, cell-communication and ultimately renal function in conditions designed to mimic DN.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: The role of Gremlin1, a bone morphogenetic antagonist, in diabetic nephropathy
Funder: Diabetes UK

Abstract: Diabetic nephropathy (DN) is the most prevalent cause of end-stage renal disease worldwide. Kidney disease accounts for 21 % of deaths in people with type 1 diabetes. Current treatments for DN such as ACE inhibitors can delay, but do not prevent the insidious progression of DN toward renal failure requiring dialysis and transplant. Therefore, there is an urgent clinical need for new and improved targets and treatments for DN. Gremlin (Grem1) is an antagonist of bone morphogenetic proteins that plays a key role in kidney development. Several recent papers from our laboratory identifying changes in Grem1 in diabetic nephropathy in humans underpin this application. The current proposal builds on these results and will address two fundamental aims. Firstly, we will determine if mice lacking Grem1 in the renal tubules are protected from diabetes-induced injury. Secondly, we will use an antibody-mediated targeting approach to determine if inhibition of Grem1 antagonism of its target BMPs can alleviate cellular damage in in vitro models of DN. Together, these strategies provide a strong basis for the development of treatment of DN in the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: Using zebrafish to implicate novel genes in the early stages of diabetic kidney disease
Funder: Diabetes UK

Abstract: An early sign of diabetic kidney disease is the presence of albumin in the urine which arises from high glucose or elevated haemodynamic forces disrupting the glomerular filtration barrier of the kidney. Recent work in our laboratory using in-bred mice has identified a set of hitherto unsuspected molecules whose expression levels in glomeruli strikingly mirror increases in albuminuria found between both strain and sexes. In this study, we will establish models of protein leakage and hyperglycemia in zebrafish, a simple organism with glomeruli similar to humans and which permits high-throughput analysis. We will test whether induction of proteinuria or hyperglycemia alters expression of our candidate genes and then modulate levels of these molecules to determine if they have a causative or protective role in these processes. These studies will allow us to examine the function of many candidate genes and pinpoint new molecules which are involved in the initiation of early diabetic kidney disease. Some of them may be new biomarkers and/or targets for future treatment for patients with diabetic kidney disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: Integration of genome-wide association, exome array and exome sequence data for diabetic kidney disease from JDRF- and IMI-funded consortia
Funder: Juvenile Diabetes Research Foundation

Abstract: To fulfil our overall objective, we aim to complete these three pieces of work: • first, we will integrate the diabetic kidney disease (DKD) GWAS data from the JDRF Diabetic Nephropathy Collaborative Research Initiative (JDRF-DNCRI) and SUMMIT-IMI efforts, through an initial round of targeted replication, and, following data harmonization, full data integration and joint analysis: these data will allow us to identify additional common variant signals of association with DKD in type 1 diabetes, and to explore their relationship to DKD in type 2 diabetes, and to other microvascular complications. • second we will integrate exome-focused data (exome genotyping data from JDRF-DNCRI; exome sequencing data from SUMMIT-IMI), through targeted replication, and following data harmonization, full data integration and joint analysis: these data will allow us to identify low frequency and rare variants which, through a direct effect on protein structure and/or function, influence DKD-risk in type 1 diabetes. • third, we will use the integrated data set generated by the first two aims to derive insights into the biological basis of DKD through a mutually-agreed program of analytical, functional and clinical research that will ensure maximum scientific and translational benefit accrues from this unparalleled resource. The results emerging from this effort will be shared with external investigators to support wider research efforts to mitigate the burden of morbidity and mortality associated with diabetic kidney disease. .


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL