NIHRDataInsights/HRCSData huggingface dataset:
Title: RAPPIDS-Rapid Assay of Pathogens with a Portable Immunosensor for Diagnosing Sepsis
Funder: Innovate UK

Abstract: Sepsis is a life threatening condition that arises when the body's response to an infection injures its own tissues & organs. An estimated 18 million people worldwide are affected by sepsis annually and In the UK the economic burden is huge with sepsis being responsible for more deaths than breast & bowel cancer combined. No clinically useful diagnostic for sepsis currently exists. This project will develop a point-of-care diagnostic assay that will allow rapid identification of the pathogen(s) responsible for the underlying infection, as well as measure levels of several key host markers, allowing the progression of the condition to be closely monitored. In turn, this will allow for the most appropriate treatments to be started at the earliest possible opportunity, leading to improved patient outcomes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Rapid, on-chip, multiplexed detection of sepsis-causing organisms from blood samples
Funder: Innovate UK

Abstract: BioGene, BG Research, and the University of Hull are working together to bring rapid, accurate testing for sepsis to the point of care. The system will identify not only the pathogen but also provide information on its antibitiotic sensitivity and in less than 1 hour, allowing the clinical team to correctly and rapidly treat the infection, saving both lives and costs to the NHS. Building on over 10 years of experience and research this innovation should reduce the impact of this life threatening condition and keep the UK at the forefront of medical diagnostics.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Validation of protein biomarkers to diagnose the early onset of sepsis
Funder: Innovate UK

Abstract: Severe infections cause widespread inflammation carried in the bloodstream (also known as sepsis) which is associated with the development of organ failure and death, and remains a significant healthcare problem. Early and accurate diagnosis of sepsis, with timely therapeutic interventions, is crucial to improved patient survival and reduced healthcare costs, but remains challenging and usually relies on intelligent clincial guesswork. The proposed project will employ a high performance protein screening platform to validate a panel of candidate protein biomarkers (with published links to sepsis) for the rapid diagnosis of patients with systemic inflammation and differentiation of sepsis cases from SIRS. If successful, the validated markers will be advanced onto an automated version of the platform to facilitate clinical use at the point-of-care, allowing clinicians to adopt innovative approaches to sepsis management to improve survival, safety, patient experience and cost efficiency.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Molecular Prognostic Test for Sepsis for use in Point of Care Setting
Funder: Innovate UK

Abstract: Diagnosis of SIRS & sepsis and identification of patients likely to progress to severe sepsis or septic shock is challenging due to a lack of definitive diagnostic tests. This project aims to identify biomarker panels for diagnosis and prognosis of SIRS, sepsis and likely progression to severe sepsis from patient host biomarkers identified in previously published studies. These will be comprehensively assessed in a combined study using temporally retrieved blood samples from a new cohort of SIRS & sepsis patients and identified using the sophisticated ANN analysis methods of NTU. Validated panels of markers will be used to build new diagnostic and prognostic ‘point of care’ and laboratory-based tests on the Atlas Genetics’ and Randox Laboratories’ platforms, which will be used to inform patient treatment and long-term care. This study is only possible through the expertise and unique collaboration between the commercial partners Atlas and Randox, the HPA, NTU, CCA and SARTRE.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: PROMPT SEPSIS : Partnership for Rapid On-site Microfluidic POC Test for Sepsis ¬¬¬
Funder: Innovate UK

Abstract: Sepsis, a severe illness in which the bloodstream is overwhelmed by bacteria, affects 18 million people worldwide annually. Symptoms can be non-specific so there are often delays in diagnosis. It is rapidly progressive illness which, if untreated can result in major organs and body systems not functioning and eventually, death. In the UK, sepsis affects up to 64,000 annually - more than breast, bowel and prostate cancers combined. Simple, timely interventions including antibiotics and intravenous fluids can halve the risk of death.Unfortunately, current sepsis tests are unreliable, especially if the onset is rapid. Tests routinely used require a blood sample to be taken and sent to the laboratory, whilst the clinician waits for the results to make a decision. PROMPT-SEPSIS proposes a low-cost, rapid point-of-care diagnostic platform using a finger prick or saliva sample to provide a rapid result to guide clinical decision-making, allowing a potentially lifesaving treatment to commence promptly.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Biomarker based cellular analysis to predict stages of infection and sepsis
Funder: Innovate UK

Abstract: Sepsis kills 30 000 people in the UK and costs the NHS £400 million per year. It is little known outside the medical profession but is the third most common cause of death in hospitalised patients outside of heart disease and cancer. It happens when an infection in the bloodstream tips the immune system out of balance and this system starts to attack the body rather than protect it. Many infections can potentially trigger sepsis but rapid treatment with the right antibiotic can often prevent it turning into serious sepsis. Even better would be to predict which patients are at greatest risk and act to protect them in advance. The Technology Strategy Board is supporting a group of teaching hospitals (Edinburgh, St Thomas’s & Newcastle) in their work with BD (a US Heathcare Company with a base in Oxford) to find a way to develop future tests which can help doctors understand which of their patients are in danger from sepsis. This will save lives and reduce the huge cost of sepsis to the NHS.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Project SABRINA (Sepsis Alert Biomarkers Resolved In a Novel Assay)
Funder: Innovate UK

Abstract: A simple, easy to use, rapid, inexpensive, effective, point of care (POC) immunodiagnostic system for early confirmation of sepsis in at-risk patients is to be developed and validated. The biomarkers will include IL-6, C-reactive protein and soluble ICAM-1. These known biomarkers will be integrated via a new algorithm with other physical/clinical indicators, and refined using a unique bank of "sepsis-risk" patient samples and controls held within the consortium, before final clinical validation. Strong pilot data gained with the markers and the sample bank gives confidence in their utility and relevance. As well as universal threshold values for each analyte, the algorithm may also be based on sequential personalised values, determined using a low-cost reader (developed outside of the proposed project) to give more accurate readings. The assay is to be based on a simple multiplexed immunoassay platform already being developed by Mologic in a parallel TSB project due to finish in April 2012.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Demonstration of a Sensor Catheter Technology for the Real Time Diagnosis of Sepsis
Funder: Innovate UK

Abstract: Severe sepsis is a major cause of morbidity & mortality, claiming up to 64k lives/yr in the UK alone; 30-50% will die as a result of the condition. There is no reliable way to prevent sepsis, and no vaccine. The key to saving lives lies in early recognition and immediate treatment. Timely identification is therefore critical. Lactate levels in blood provide an indication of the level of sepsis in a critically ill patient. Antibiotics are used to lower lactate levels. 43% of patients die if lactate clearance takes more than 24 hours. Current treatment methodologies are time consuming (taking/analysing blood samples). This project aims to demonstrate the effectiveness of a novel type of vascular catheter technology for the measurement of sepsis through the real time detection of lactate in blood, through targeted laboratory & patient trails. This innovative on-line solution will improve treatment response times to potentially avoid detrimental impact on internal organs, benefitting patients globally.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Immunomodulatory effects of pre- and probiotics
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Immunosenescence is a gradual deterioration and dysregulation of the immune system during ageing. It results in increased susceptibility of older subjects to infection and renders vaccination less effective. Probiotics have been suggested to strengthen specific and innate immune responses in healthy individuals, to reduce the duration and severity of respiratory infections in both the old and the young, and to augment the antibody response to influenza and polio vaccination. However, it is not clear whether probiotics are able to specifically improve the function of immunosenescent cell populations in older subjects. The proposed project will involve 60 young and 60 older subjects, who will take a pre- and probiotic mixture or a placebo for a total of 8 weeks. The probiotic is not currently commercially produced, but has been demonstrated to have particular ecological fitness and anti-pathogenic effects in the gastrointestinal tract in old age. A suitable prebiotic will be selected on the basis of ability to promote optimal growth and survival of this probiotic. After 4 weeks on the treatment, the subjects will receive an influenza vaccination. Blood samples will be taken before treatment, and at 4, 6 and 8 weeks after commencement. A wide range of immune parameters will be assessed, taking into account the age-related shifts in immune cell populations. In conjunction with the human study, a series of in vitro studies will investigate the mechanistic basis for the impact of the probiotic on immune function and will determine whether there are differential effects of the probiotic in young and older subjects at the cellular and molecular level. The proposed project will demonstrate for the first time whether pre- and probiotics are of particular benefit in older individuals by modulating the impact of immunological ageing.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Opportunity-Led Research Proposal: Detection of Sepsis Pathogens Award
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Collaborating with a multicentre clinical group in the UK, led by McMullan and McAuley from Queen's University Belfast, Randox will develop a multiplex PCR-biochip array to enable discrete detection of >40 sepsis-associated pathogens within 1 hour. Randox have secured previous TSB funding to design a POC device for multiplex sexually transmitted infection detection. By enhancing the automated extraction, amplification and detection capabilities of this device, introducing an advanced cartridge design, we will develop innovative technology to identify sepsis agents from clinical samples, including blood. This adds significant value to previous TSB funding. This test will enable immediate, tailored patient management at the point of care, at presentation. No current technology can meet this critical need. Combining clinicians with expertise in sepsis and technological capabilities from Randox, this consortium will develop a POC test to match clinical need and ensure its commercial success.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: HIV/HCV Co-Infection: Use of Peripheral Blood and Hepatic Interferon Stimulated Gene (ISG) expression to select and stratify patients for antiviral treatment.
Funder: Department of Health (England)

Abstract: Patients with HIV and Hepatitis C (HIV/HCV) experience more aggressive liver disease and are much less likely to achieve a cure with the standard treatment of pegylated-Interferon/ribavirin (PEG-IFN/RBV) than those with HCV infection alone. In patients with HCV, high levels of interferon-stimulated genes (ISGs) in the liver are associated with a low chance of cure with PEG-IFN/RBV but this has never been studied in patients with HIV/HCV. We will compare ISG levels in HIV/HCV patients with HCV patients and investigate whether ISG levels in blood or liver can predict treatment response to PEG-IFN/RBV containing therapy in HIV/HCV infection.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Pattern recognition receptors and the recruitment and differentiation of myeloid cells in inflammation.
Funder: Medical Research Council

Abstract: The primary aims of this research are: i) to determine the importance of the leukocyte beta-glucan receptor, Dectin-1, in the regulation of myeloid cell recruitment, activation, differentiation and survival during fungal infection; and ii) to develop novel models for the study of myeloid cells during inflammation. Our initial characterisation of the leukocyte ?-glucan receptor, Dectin-1, has shown that it is broadly expressed on myeloid cells and plays a fundamental and non-redundant role in the recognition and response to fungi. Deficiency in Dectin-1 results in susceptibility to Candida albicans infection and this is associated with defective inflammatory responses. The increasing prevalence of fungal infections associated with acquired immunodeficiency and medically induced immunosuppression and the importance of Dectin-1 in anti-fungal defence have highlighted Dectin-1 as a potential therapeutic target. It is important to understand how Dectin-1 regulates the anti-fungal inflammatory response to appreciate novel ways of manipulating the cellular response during inflammation. To achieve the aims of this proposal we will also develop models for the study of myeloid cell biology during inflammatory responses. These models will be important, not only for the study of the role of Dectin-1 in inflammation but also as a basis for improving the study of myeloid cells in models of human disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Acute dendritic cell responses to TLR ligands
Funder: Medical Research Council

Abstract: Dendritic cells (DC) are now recognised as key immune cells that detect infectious microorganisms through various pattern recognition receptors and translate these ?innate? immune signals into an ?adaptive? immune response. Much recent work has focussed on responses made by Toll-like receptors (TLRs) whose signalling leads to increased expression of cytokines and co-stimulatory molecules. However TLR signalling also triggers a number of striking cell biological changes in DC, some within minutes. We recently showed that LPS and other TLR ligands induce an acute upregulation of actin dependent endocytosis leading to enhanced antigen capture and presentation and simultaneously, a transient loss of F-actin rich podosomes. In this proposal we wish to follow up our latest findings that activation of the MAP kinase activated kinase RSK is crucial for this endocytic response and surprisingly, that the ?wiring? of the MAP kinase pathway is different in DC . In DC we found that RSK can be activated by Erk, as in most cells, but also by a novel p38 MAP kinase pathway. We propose projects which aim to discover what other DC responses RSK is involved in, what its key substrates are, how p38 is able to activate RSK, what the significance of this might be and what roles the other MAP kinase activated kinases (MSK1/2, MNK1/2 and MK2/3) may play in DC. We also propose studies to probe the significance of podosomes in DC and their regulation by TLR signalling. Podosomes are intriguing structures that are thought to be involved in cell migration and invasiveness. A key feature of podosomes and related structures called invadopodia is their ability to organise matrix metalloprotease (MMP) activity. We have recently found that DC podosomes engage in focussed pericellular proteolysis and that this is due to the enzyme MT1-MMP. Intriguingly, TLR-ligand induced podosome disassembly requires MMP activity, but this is due to a second unidentified enzyme. Because TLR signalling regulated MMP activity is likely to be important for DC migration though tissue and matrix barriers we propose to identify the second MMP activity and assess what roles these two MMPs play in DC migration in vivo. Finally, we propose various cell biological studies on DC podosomes and in particular an analysis of their structure at the EM level which we think will both clarify their relationship to invadopodia and help us to assess their role in DC in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Hantavirus reverse genetics and innate immune responses
Funder: Medical Research Council

Abstract: Hantaviruses comprise one genus within the family Bunyaviridae and include some of the most important human pathogens in that family, including those causing haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Hantaviruses have a worldwide distribution and are recognised as posing an increasing threat to human helath. Despite the significant medical impact of hantaviruses, many aspects of their replication and interaction with host cells are incompletely understood. A major impediment to the study of hantaviruses is the lack of a reverse genetics system. In addition, hantaviruses grow less well in tissue culture compared to, for example, orthobunyaviruses, presenting technical difficulties. Thus, in this project we will (a) investigate cell lines that should allow improved growth of hantaviruses; (b) develop reverse genetics systems for hantaviruses; (c) investigate aspects of hantavirus RNA synthesis; (d) attenuate hantavirus replication in cell culture via reverse genetics; and (e) investigate the interactions of strongly pathogenic, weakly pathogenic and apathogenic hantaviruses with host innate immune systems These studies will lead to an increased understanding of hantavirus replication and lay the foundation for future work to develop novel hantaviruses as potential vaccines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Role of the secretory pathway in HIV-1 egress from T cells
Funder: Medical Research Council

Abstract: The aim of this project is to establish the role of the secretory pathway in HIV-1 egress from T cells. Evidence from model, non-lymphoid systems indicates that HIV-1 hijacks elements of secretory pathways to transport viral proteins and coordinate virus assembly, but almost nothing is known about HIV-1 assembly and egress in primary CD4+ T lymphocytes. Haematopoietic cells are unusual because in addition to the ubiquitous constitutive secretory pathway, they contain specialised organelles transported via regulated secretion in response to stimuli such as cell-cell contact. A regulated secretory pathway exists in CD4+ T cells, but little is known about the cellular compartments involved, or the triggers for activation of secretion. By contrast, molecules involved in regulated secretion by CD8+ T cells at the immune synapse are well characterised and may provide clues about factors mediating HIV-1 assembly in CD4+ T cells. The key goals of this project are to: i) broadly characterise how CD4+ T cells traffic cellular and viral proteins via constitutive and regulated secretory pathways; ii) identify cellular and viral molecules controlling regulated secretion in CD4+ T cells; iii) evaluate the contribution of CD4+ T cell secretory pathways to viral dissemination between T cells, and to investigate strategies of inhibition. Experiments designed to dissect the secretory pathway in CD4+ T cells and its subversion by HIV-1 will be performed using cells from normal individuals, and from individuals with defined genetic defects in molecules that control the transport and release of secretory lysosomes from CD8+ T cells. Immunofluorescence confocal microscopy and electron microscopy, subcellular fractionation and biochemical analysis will be employed to colocalise HIV-1 with molecules that undergo regulated secretion from CD4+ T cells. Emphasis will be placed on transport of the viral glycoprotein Env, and characterisation of associated compartments, as less is known about Env trafficking and Env incorporation is absolutely required for viral infectivity. The cellular cytoskeleton is intimately linked with secretory pathways, immune cell interactions and is implicated in HIV-1 egress and spread. To identify novel proteins involved in the intracellular transport of Env and Gag and virus assembly a siRNA screen will be performed targeting kinesin, dynein and myosin molecular motors. By identifying cellular factors that regulate HIV-1 egress and dissemination we aim to achieve a greater understanding of HIV pathogenesis that should open up opportunities for design of novel therapeutic agents to treat HIV/AIDS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION