NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of enteropathy in the pathogenesis of severe acute malnutrition in HIV-infected African children
Funder: Medical Research Council

Abstract: In sub-Saharan Africa, around one-third of children hospitalized for severe acute malnutrition (SAM) have underlying HIV infection, and HIV has transformed the epidemiology, clinical presentation and outcome of SAM. Mortality in children with HIV and SAM (termed HIV-SAM) is 4-fold higher than in children with SAM alone, for reasons that remain unclear. Both HIV and SAM are characterized by intestinal damage (enteropathy). Intestinal barrier function is critical to health, and loss of this structural and functional barrier enables translocation of intestinal bacteria and proinflammatory molecules to the systemic circulation. We believe that breakdown of the intestinal mucosal barrier is an often-overlooked pathological process underlying SAM, and that the combined impact of HIV and SAM leads to more severe and extensive enteropathy and slower mucosal recover. We will recruit children with SAM HIV-SAM and well-nourished controls from three sites in Zambia and Zimbabwe, to characterize the enteropathy of SAM and HIV-SAM. A longitudinal series of investigations will compare gastric and small intestinal barrier function. In a subgroup with severe symptomatic enteropathy, endoscopy and biopsy will allow detailed assessment of gut architecture, correlation of structure and function, and investigation of the causes of persistent diarrhoea. To investigate the extra-intestinal consequences of enteropathy, we will first compare the microbial composition of the upper gut and plasma using deep sequencing, to determine whether translocation of enteric organisms underlies sepsis and pneumonia in malnourished children; and, second, characterize gene expression profiles to determine whether differences in host inflammatory response underlie the increased morbidity and mortality of HIV-SAM. Overall, this study will provide a rationale for a future trial of interventions to restore mucosal integrity, block microbial translocation and lower chronic inflammation to reduce mortality.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: Chlorhexidine Nanoparticles in the Management of Peri-implant Diseases
Funder: Medical Research Council

Abstract: Background: Dental implants can be affected by peri-implant bacterial infection, which may result in bone loss and implant failure. Aims: To determine whether chlorhexidine hexametaphosphate nanoparticles (CHX-NPs) have potential for use as an implant coating to prevent peri-implant infection. Objectives: 1. Apply a discrete, non-continuous CHX-NP coating to titanium 2. Investigate the antimicrobial efficacy and mechanism of the coating 3. Establish effects of the coating on osteoblast colonisation, growth and maturation Methods: A CHX-NP coating will be applied to titanium coupons prepared to mimic a dental implant surface. Reactant concentrations, deposition parameters and aggregation control will be optimised for even coverage, assessed using SEM, TEM and AFM. Duration and level of CHX release will be characterised using UV spectrophotometry. Antimicrobial efficacy of the coating will be assessed using clinically isolated microbes. TEM will identify potential mechanisms of bactericidal action, and will direct proteomics to identify changes in marker proteins/genes. A polymicrobial biofilm flow cell will be used with human saliva. FISH assay will elucidate temporal changes in biofilm. HMSCs will be differentiated into osteoblasts and used to establish the effects of CHX-NP on osteoblast adhesion, metabolism, growth, proliferation, differentiation and toxicity. Dose-response of outcomes, and thresholds for adverse effects will be established. Results from objectives 2 and 3 will inform changes to the coating to establish an ideal CHX release profile. Scientific/medical opportunities: This research will elucidate the scope for CHX-NP coatings to be adapted for biomedical devices. It will identify the antibacterial mechanism of action of the coating, and reveal any toxicity towards human osteoblasts. These findings have potential to facilitate development of a CHX-NP coating for dental implants, and advance progression towards in vivo trials.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: IMPC: P2X7R dependent regulation of gut immunity
Funder: Medical Research Council

Abstract: Our gut is a major site where infections can occur such as those caused by food poisoning. Having a healthy gut lining or barrier helps protect us against "bad" food borne bacteria. As well as protecting against bad bacteria and other infections, our gut is full of "good" bacteria - the microbiome- and these good bacteria help us digest our food and even keep our gut barrier healthy. Although these bacteria are helpful to us, if our body's defence system is not properly regulated we may react inappropriately to the bacteria which causes inflammatory bowel disease. The cells that line our gut, the epithelial cells, are really important to decide when the gut needs to ignore something that helps it, like the microbiome, and when we need to switch on the body's defence system to get rid of an infection. A big difference between an infection and the normal microbiome is that infections cause lots of damage to the gut. The damage causes lots of substances to be released and epithelial cells and defence cells can see these damage signals and then switch on the body's defence system. Equally, understanding how damage substances switch on the defence system can be useful in making drugs and vaccines work better for us and the animals around us. We will study how damage substances switch on or activate epithelial cells to make them respond to infection. We have identified that a receptor -P2X7R -in the gut lining can recognise the damage caused in infection and switch on the body's immune system. Immune cells also have this specialised receptor but our work suggests it works differently in immune cells to epithelial cells. We will use a transgenic mouse model that lacks this receptor only in the epithelium to dissect how the gut epithelium is responding to infectious stimuli and our friendly bacteria. Once we know how epithelial cells sense infection we can develop strategies to better tackle common infections and may even help diseases that cannot currently be cured such as IBD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: The role of bile-metabolising enzymes in the pathogenesis of Clostridium difficile infection, and the impact of faecal microbiota transplantation.
Funder: Medical Research Council

Abstract: Antibiotic use is the major risk factor for Clostridium difficile infection (CDI), although the exact pathogenesis of the condition is unclear. Conversely, whilst faecal microbiota transplantation (FMT) is an effective therapy for CDI, its mechanism of action is unexplained. In vitro, conjugated primary bile salts promote C. difficile's germination, whilst unconjugated secondary bile salts inhibit its vegetative growth. In vivo, bile salt hydrolases (BSHs) are enzymes secreted by selected bacteria in the healthy gut microbiota which deconjugate primary bile salts. This project hypothesises that antibiotic-related loss of BSH-secreting gut microbiota predisposes to CDI by enriching conjugated primary bile acids within the gut (and consequent germination and growth of C. difficile), and that FMT reverses this process. We will firstly compare stool and urine samples collected from people treated successfully and unsuccessfully for CDI with FMT both pre- and post-transplant. Assays will be performed for gut microbial profiling/ metataxonomics (via 16S rRNA sequencing), bile acid/ general metabolite profiles (via mass spectrometry/ NMR), and for BSH expression and activity (via qPCR, and a plate-based functional assay respectively). Analyses of these data will identify culprit BSH-producing organisms responsible for restoration of normal bile acid metabolism post-FMT. The next phase of work will be a functional analysis of these BSH-producing bacteria. Co-culture experiments between BSH-producing organisms and C. difficile spores (in the presence of a bile pool milieu similar to that found in vivo) will define the effect of these bacteria upon C. difficile's germination. Finally, CDI will be modelled with an in vitro distal gut system (chemostat); the 'real time' effect of addition of a defined microbial community of BSH-secreting organisms upon this system will be examined, exploring changes in microbial and bile acid profiles, and in C. difficile viability.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: Public health and primary care: targeting antibiotic use and preventing chronic liver disease
Funder: Department of Health and Social Care

Abstract: Aim: To build on our research strengths to address two important public health problems: i) targeting antibiotic use to those who need it and ii) preventing chronic liver disease by addressing alcohol misuse and hepatitis C infection.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: MICA: Development of new agents for the treatment of cryptosporidiosis
Funder: Medical Research Council

Abstract: Cryptosporidiosis is one of the most significant causes of death and illness from diarrheal diseases amongst children in the developing world, as found by the Global Enteric Multicenter Study (GEMS), a case-control study conducted at 7 sites in Africa and South Asia, the most comprehensive study to date. It is the major contributor to life-threatening diarrhea in young children, with 2.9-4.7 million cases in children < 24 months in sub-Saharan Africa and the Indian sub-continent, leading to >200,000 deaths per year. Cryptosporidiosis is also associated with malnutrition and stunted growth in children and probably causes chronic infections. Nitazoxanide, the current treatment for the disease, has poor efficacy and is not effective in immunocompromised patients. There is an urgent need for the development of new drugs to treat: (1) children <24 months, especially those that are malnourished and with chronic diarrhea; and (2) immunocompromised children and adults with advanced AIDS and chronic diarrhea. Cryptospordium may be the cause of as much as 75% of chronic diarrhea in this patient cohort. We have developed a series of orally efficaceous compounds in two mouse models of cryptosporidiosis, demonstrating great potential to treat the disease. This series has been discovered through a structurally enabled programme for lysyl t-RNA synthetase. The series has been declared an "early lead" by the Scientific Advisory Board of the Structure Guided Drug Discovery Coalition. The aim of this project is to optimise the series to identify a preclinical candidate, orally active in appropriate animal models of infection (rodent and calf) and overall good developability properties for progression towards the clinic. This will involve optimising the compounds for potency against the parasite; for pharmacokinetics to ensure optimal compound delivery to the sites in the body where parasites reside; and for appropriate safety margins.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: Dysbiosis of the oral microbiome in periodontal disease: host gene and pathogen effects
Funder: Medical Research Council

Abstract: The investigation addresses the hypothesis that dysbiosis of the oral microbiome, induced by either the genetic status of the host or by the introduction of periodontal pathogens leads to the development of inflammatory periodontal disease mediated through the normally benign oral microbiome. Understanding of the involvement of dysbiosis of the periodontal microbiota in the aetiology of disease has been hindered by the absence of a suitable animal model which allows study of the influence of the microbiome in a well characterised host genetic background. The aims capitalise on recent findings using the mouse model of periodontal disease. 1. Characterise the oral microbiome of the mouse by sequence analysis of 16S rRNA genes representative of orally adapted mouse bacteria using Sanger sequencing of cloned libraries. The data will provide a reference database of the mouse oral microbiome which will be made available to the periodontal research community 2. Use high throughput pyrosequencing (Roche 454 platform) to analyse dysbiosis of the mouse oral microbiome caused by ageing and by the introduction of low levels of Porphyromonas gingivalis, acting as a keystone bacterial pathogen, and to correlate these changes with the development of periodontal bone loss 3. To determine the influence of host genetics on dysbiosis of the mouse oral microbiome by analysis of the microbiota of mouse knockouts in genes shown to increase susceptibility to periodontal bone loss (CXCR2-/-and LFA-1-/-) and also those known to be protective (C5aR-/- and TLR2-/-) 4. To determine the efficacy and influence of transmission of disease-associated and disease-protective microbiomes into germ free animals on periodontal bone loss. The data will provide the basis for understanding the effects of changes which occur to the microbiome in human periodontal disease and will potentially identify those bacterial species which are responsible for the disease and those which may be protective.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: eGUT: a Tool for Predictive Computer Simulation of the Gut Microbiota and Host Interactions
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: We propose the development of a generic computer simulation tool to reduce and replace animal experiments by simulating the gut microbiota and their interactions with the host. This tool, called eGUT, will be built by extending the individual-based Dynamics of Microbial Communities Simulator iDynoMiCS, which we have developed with many colleagues and published in Environmental Microbiology last year and made available as open source on www.idynomics.org. Using an individual-based model (IbM) as the engine for the tool has the advantage that the tool will be very flexible, e.g., the number of species or the types of interactions or the rules of behaviour can be chosen by the scientist user - as required of a generic tool. Moreover, IbMs merely describe the activities of the individual organisms or host cells. Their behaviour is described by equations for the kinetics of growth and by rules for cell division (if larger than threshold divide) and other decisions. These kinetics and rules are typically based on laboratory experiments under defined conditions. It is quite important to realize that simple rules can lead to complex dynamics and spatial patterns so that complexity of a system does not mean that it cannot be understood or modelled because it is too complex. Complexity simply emerges from the multitude of local interactions of various individuals with the environment and with the host cells, as running an IbM will demonstrate. The gut microbiota has profound effects on our health, a realization leading to a surge of animal experiments in this area, so that the development of a computer simulation tool to reduce or replace these animal experiments is a gap that is becoming increasingly urgent to fill. Our specific aims are to build eGUT, apply eGUT to model the spread and replacement of antibiotic resistance plasmids in the gut, apply eGUT to two further test cases from our collaborators, and to disseminate eGUT to actively increase the user base.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: Towards engineering a multi-cell lineage multi-organism intestine
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: This proposal is aligned to two of the NC3R’s objectives, namely the Replacement and Reduction of animals in research. The establishment of a system whereby the gut can be recapitulated in vitro will have serious impacts upon the number of animals required for use in research. The intestine fulfils critical roles for life. Its physiology and homeostasis requires complex cellular and molecular interactions. Gene-targeted mice and infection models have provided important insights into enteric physiology, but the complexity of the in vivo system hinders detailed study of cellular and molecular components and requires the use of large cohorts of model animals to observe statistical differences. We will adapt organoid cultures (a rudimentary gut) to incorporate cells critical to intestinal homeostasis. This enables the study of interactions of immune cells with gut-epithelial cells, important in tissue turnover and repair, in great detail and with minimal use of model animals and without regulated procedures. To meet the challenge of complexity and future use of the system, we will use interdisciplinary approaches at the interface of immunology, microbiology and bioengineering. This will form the basis for the development of highly organized intestines with sealed enteric luminal and basolateral sides, ensuring the full development of a 3D multi-organism artificial intestine. This enables the study of the gut in steady state and in varying contexts of growth factors, dietary compounds, micro-organisms and immune cells. The challenge to create sealed luminal and basolatheral sides does not preclude the study the interactions of the epithelial cells with micro-organisms We will initiate this by using conserved micro-organismal products and test their effect on cells of the intestine in the absence and presence of immune cell subsets. We will also test the suitability of the system in providing the correct conditions for the full lifecycle of intestinal parasite species which critically rely on host factors in the intestine.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: What is the molecular contribution of platelets to liver injury in hepatitis?
Funder: Wellcome Trust

Abstract: Deaths from liver disease have been progressively increasing over the last three decades, with the death rate up eight times in men and seven times in women. Liver damage occursdue to a variety of reasons including alcohol, obesity, immune disease and infections. Most liver damage heals with little or no long term damage, however persistent injury causes irreversible liver scarring, liver cancer and end stage liver disease. The only cure at this point remains aliver transplant. Why the liver responds to some insults by healing itself andbecomes irreversibly damaged to others remains unclear. Blood cells known as platelets may help explain this. Traditionally thought to only have a role in stopping blood loss by aiding clot formation, platelets have now been found to have wider roles in health and disease. Recent research has shown platelets todrive the development of liver disease with antiplatelet drugs like aspirin reducingliver damage. Very little is known about how platelets damage the liver, or which specific aspects of theirfunctioning are critical to liver disease. Using specialized mice models and liver expertise available in Birmingham we hope to understand how platelets cause liver damage and thus help develop new treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL
Title: T cell assay for BK virus infection in transplant patients
Funder: Innovate UK

Abstract: BK virus is endemic in the UK adult population. Although it causes little or no disease in healthy people the virus is known to persist in the kidney in particular. Reactivation of the virus is linked with immune suppressive conditions and this reactivation occurs in around 20% of kidney transplant patients and can lead to significant damage to the transplanted organ. While the level of the virus itself can be measured there is currently no test available that indicates whether or not the patient is able to fight off the infection successfully through their T cell response. This project is therefore aimed at proving the principle for the design of such a test so that kidney transplant recipients can be managed for the infection more effectively, leading to less transplanted organ loss due to this infection.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;RENAL AND UROGENITAL
Title: Optical and Drug Techniques in reducing Urinary Catheter Blockages
Funder: Innovate UK

Abstract: Vodus Medical a company involved in developing optical products for the healthcare market are developing a novel urinary catheter which offers reduced complications from blockages and infections. Research In the Oral & Dental Sciences Research Group, at the University of Central Lancashire, complements the objectives of this proposal and as such can benefit from the local academic environment and the expertise it has to offer.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: INFECTION;RENAL AND UROGENITAL
Title: Developing a theory-based intervention to reduce the duration of urinary catheterisation and associated urinary tract infections in primary and secondary care settings.
Funder: Department of Health (England)

Abstract: Combating Catheter-Associated Urinary Tract Infection (CAUTI) is a priority in the world-wide drive to reduce hospital acquired infections. Minimising duration of catheterisation is an effective method of reducing CAUTI but implementation of early catheter removal requires a change in the standard practice. This study will identify factors that delay or encourage catheter removal from both a patient and health care professional (HCP) behavioural perspective using qualitative analysis of semi-structured interviews and quantitative analysis of questionnaire responses with both groups. The project design aligns with the MRC framework for the development of complex interventions. The findings will inform development and piloting of a behaviour change intervention, for patients and/or HCP aiming to reduce catheter duration and lessen the risk of CAUTI in both community and hospital care settings.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION;RENAL AND UROGENITAL
Title: Highly active antiretroviral therapy: effects on renal function and optimal use in end-stage renal disease and renal transplantation
Funder: Department of Health (England)

Abstract: Widespread use of highly active antiretroviral therapy (HAART) for treatment of HIV has dramatically improved the health of infected individuals. However, it has emerged that ageing HIV patients are at increased risk of kidney and bone disease and that HAART may adversely affect this risk. This fellowship will study the effects of HAART on renal function, risk factors for developing kidney disease, management of HIV infection in the presence of kidney disease and evaluate renal transplantation as treatment for end-stage kidney disease in HIV. It is envisioned that opportunities to prevent severe kidney disease in HIV infection will be identified.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;6.1 PHARMACEUTICALS
Health categories: INFECTION;RENAL AND UROGENITAL