BJA/RCoA Non-Clinical PhD Studentships

University of Edinburgh

Title
Mapping and manipulating the human neutrophil response to staphylococcus aureus

Amount
£99,342

Scientific Abstract
Staphylococcus aureus is a major human pathogen, causing infections at multiple sites including the lungs and surgical sites. Although of major interest as a hospital-acquired pathogen, it also contributes to a significant burden of community-acquired infections. The neutrophil forms the first line defence of the immune system against invading pathogens. Understanding the pathways by which neutrophils interact with this pathogen and what happens when neutrophils are rendered dysfunctional will offer novel insight into the pathobiology of infections and offer the prospect new non-antibiotic therapies. My group has previously established a major role for the complement component C5a in driving neutrophil dysfunction in critically patients and shown this is associated with subsequent development of infection. We have developed several in-vitro models of Staphylococcal bacteraemia and demonstrated that C5a impairs the phagocytosis and killing of this pathogen. In preliminary experiments, we have developed a high-resolution neutrophil phosphoproteomic technique which has identified several candidate pathways activated by S. aureus, two of which appear to be modulated by C5a. The aim of this project is to characterise the neutrophil phosphoproteomic response to S. aureus over time, examine how these pathways are perturbed by C5a and their susceptibility to manipulation by pharmacological and transcriptional alteration.

University of Aberdeen

Title
Interactions between melatonin and endogenous opioid peptide release

Amount
£89,426

Scientific Abstract
Control of pain remains a challenge for medicine. Melatonin, known for its role in circadian regulation, also has antioxidant and anti-inflammatory actions and has been suggested to have analgesic effects in a range of pain syndromes. Our own work showed that melatonin treatment reduced pain behaviour in a rat model of neuropathic pain. Both melatonin and endogenous opioid peptides ('endorphins') are released by immune cells and pituitary cells as part of neural-immune interactions, contributing to endogenous analgesia. We have shown that melatonin treatment augments endorphin release from pituitary cells. In this studentship we propose to investigate in detail the extent of the interaction between melatonin and endorphins as a potential mechanism for analgesic effects of melatonin, using macrophages and pituitary cells. The effects of melatonin treatment on the endogenous opioid peptide profile of patients with chronic pain will also be determined. This project will determine if melatonin-endorphin co-regulation is a credible mechanistic explanation for the effects of melatonin on pain.

Queen Mary University of London

Title
Characterisation of metabolic dysfunction and altered T cell migration in lymphopaenic perioperative individuals

Amount
£92,481

Scientific Abstract
Lymphopaenia is a common finding in older individuals, yet is commonly perceived to be of no clinical significance. However, perioperative lymphopaenia has repeatedly been shown to be strongly associated with an increased risk of postoperative complications, including infections, and delayed hospital discharge. We wish to explore the role of immunosenescence in perioperative lymphopaenia. Senescence and ageing are inextricably linked, with senescent cells displaying impaired function together with a hyperinflammatory secretory profile. We postulate that this proinflammatory T-cell phenotype promotes organ injury through the redistribution of injurious T-cells to vulnerable organs.

Metabolic dysfunction underpins the immunosenescent phenotype of T-cells, resembling the bioenergetics changes observed in postoperative T-cells. By serial immunophenotyping and metabolic profiling of T-cell subsets pre- and postoperatively, we will establish whether there is a link between senescence, lymphopenia and poor surgical outcomes. We will also assess whether preoperative lymphopaenia is associated with senescent lymphocytes being redistributed into tissues (synovial tissue obtained during surgery). Finally, we will investigate if postoperative lymphocytes display altered responses to standardised ex-vivo challenges, and see whether the inflammatory state can be reversed through metabolic manipulation. This is important as millions of older individuals undergo surgery each year, but struggle to return to independent function.

St Thomas' Hospital, London

Title
Studying immune trajectory to determine optimal timing for immunomodulation in sepsis patients: Scientific cohort study

Amount
£89,331

Scientific Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Major components of these dysregulated host responses are immune system alterations. Both innate and adaptive immune systems are acutely altered and determine the outcome following sepsis-related critical illness. To-date, these immunological abnormalities are characterised mostly at admission day with very few studies exploring changes over the hospitalisation period. However, it is conceptualized that these immunological abnormalities differ between patients, change over time (trajectory), contribute to immunosuppression and explain the negative clinical trials of immune interventions in sepsis. Understanding the right intervention to give at the right time to sepsis patients is important since sepsis incidence is increasing, ~30% of sepsis patients die in hospital and patients who survive this illness are left with longer term health care risks that exceed general population norms. We hypothesise that systems-level analysis on longitudinal (repeated) measurements of 29 key lymphocyte markers using mass cytometry plus quantification of 92 immune response signalling proteins will reveal the main patterns of immune trajectory (immune deterioration and immune recovery). We aim to describe the immune response patterns in sepsis and their relationship to outcome in sepsis-related critical illness.