2017-18 Grant Awards

Open-call grant awards

The William Harvey Research Foundation is delighted to award grants to the following William Harvey Research Institute researchers:

Principal Investigator: Dr Julie Borgel, Translational Medicine and Therapeutics
Study title: Trauma induced DNA methylation signatures - a novel prognostic biomarker and therapeutic target for post-traumatic acute and chronic immune dysfunction

  • Award: £9,911 Consumables

As the immediate treatment given to severely injured ‘trauma’ patients continues to improve, more and more patients that previously would have died either at the scene of the accident or shortly afterwards, are now surviving. These patients require ongoing care in an Intensive Care Unit (ICU) and now are much more likely to die from infections contracted in the ICU than to die directly from their injuries. Frequently these are young, previously healthy people and it is unclear why they are so susceptible to normally innocuous infections. Our goal is to understand the molecular mechanisms which predispose trauma patients to opportunistic infection. This project will use blood samples obtained from trauma and major surgery patients to explore how severe injuries and tissue damage disrupt the regulation of crucial immune-related genes. We will focus our research on an essential chemical modification of DNA that can affect how and when genes are switched on and off. The ultimate aim is to develop novel prognostic and therapeutic approaches in order to detect and reduce the development of post-traumatic infectious complications.

Principal Investigator: Professor Francesco Dell'Accio, Centre for Experimental Medicine and Rheumatology
Study title: The mode of action of a new therapeutic target tyrosine kinase receptor in osteoarthritis

  • Award: £49,325 Post-doctoral fellowship

Osteoarthritis is a leading cause of disability. Osteoarthritis is caused by loss of the cartilage from the joints and causes pain and loss of mobility. Patients struggle walking, cooking, or dressing themselves. Joint replacement is often necessary, but is a difficult operation and prostheses only last about 15 years. We discovered that blocking a molecule on cartilage cells and stem cells results in the formation of more cartilage. Blocking this molecule protected mice with osteoarthritis from pain and further cartilage loss. We still do not understand how this molecule works. We know that it adds a chemical modification (a phosphate group) onto other molecules in the cell, but we do not know which ones. Using a biochemical technique, we will simultaneously analyse every protein in the cells and see if activation of this receptor adds phosphate groups to them. We will then verify if these molecules interact with each other. Understanding the mode of action will make this approach appealing to pharmaceutical industries and would enable clinical trials because it would allow us to easily determine the dose of the blocking agent which adequately suppresses the function of this molecule.

Principal Investigator: Dr Fiona Lewis, Centre for Microvascular Research
Study title: Exosomal microRNAs as diagnostic biomarkers of heart failure

  • Award: £9,938 Consumables

Heart failure (HF) is a leading cause of death in the UK and worldwide. At present there is no single diagnostic test for HF therefore new biomarkers are required to enable early diagnosis and provide efficient methods of monitoring/treating HF. In recent years, miRNAs have emerged as a potentially valuable diagnostic tool for damaged hearts. However due to considerable variability in patient cohorts and methods of detection, a lack of reliable evidence for the use of miRNAs as biomarkers for HF persist. Exosomes are nanosized particles capable of transferring molecules, including miRNA, to neighbouring cells. Due to their unique biology, exosome miRNA expression level changes appear to be more specific to disease states than total circulating miRNA. In this study we will determine how exosome-derived miRNAs can provide a reliable biomarker of HF. Exosomes will be isolated from healthy age-matched controls and HF patient serum and miRNA screening performed to identify disease-specific miRNA signatures that can be utilised as novel diagnostic/prognostic biomarkers thus having major impact on the future treatment of heart disease and failure.

Principal Investigator: Professor Mauro Perretti, Centre for Biochemical Pharmacology
Study title: The development and characterization of pro-resolving therapeutics as novel anti-inflammatory drugs

  • Award: £3,593 Consumables

In 2002, we published a ground-breaking study demonstrating, for the first time, that the anti-inflammatory actions of the natural hormone adrenocorticotrophin were retained in adrenalectomized rats, and possibly mediated by the melanocortin (MC) receptor subtype 3. That work prompted a new line of research on peripheral anti-inflammatory melanocortin receptors and their agonists, which we have been deciphering for over a decade, making a fundamental contribution to the field. Anti-inflammatory actions of MC drugs have been observed in a number of animal models including experimental models of arthritis, colitis, renal injury, ischemia-reperfusion, and brain damage.

We are working on a number of projects in close collaboration with industry as well as Arthritis Research UK (ARUK) to develop and characterize novel drugs that target the melanocortin system to produce anti-inflammatory effects. More specifically, we are characterizing the molecular mechanism of action of two novel peptides developed by Palatin Technologies, as well as six novel peptides produced by TXP Pharma. In addition, we are co-funded by ARUK for in-house production and pre-clinical development of a novel antibody therapeutic for the treatment of rheumatoid arthritis.

Our Foundation grant will support the acquisition of new equipment to help with these projects. We will acquire equipment related to routine lab bench work, histology, immunofluorescence techniques, and bacterial culture. This equipment will also benefit a variety on other projects (some of which originally funded by the Foundation) based on the concept of Resolution Pharmacology focusing on Annexin A1, its receptor and peptides; Galectins; sex hormones and microvesicles for regenerative medicine.

Principal Investigator: Professor Chris Thiermermann, Centre for Translational Medicine and Therapeutics
Study title: The role of MIF in trauma-associated haemorrhagic shock

  • Award: £99,986 PhD studentship

Trauma is a worldwide health problem and is increasing in both incidence and severity. As a relatively new field, with relatively little attention, there are many opportunities to explore the biology and pathophysiology of injury. Trauma can act as a model for other disease types, especially as the time and severity of insult are both known and accessible. Severe injuries account for 9 % of deaths worldwide. Although guidelines for the early management of severe blood loss after trauma have decreased the rates of immediate (on scene) and early (emergency department) deaths, post-injury multiple organ failure (MOF) is still associated with significant morbidity and mortality. Treatments that reduce the incidence and severity of MOF following blood loss could, therefore, have a major global impact on patient outcomes and healthcare costs, but are currently not available. Macrophage inhibitory factor (MIF) is a messenger protein that is raised in patients with trauma/blood loss, which may drive excessive inflammation and organ injury. This study is designed to gain a better understanding of the MIF-family of proteins in patients with trauma and in experimental, severe blood loss and will test the effects of a new treatment to block the effects of MIF in trauma.

Principal Investigator: Dr Mathieu-Benoit Voisin, Centre for Microvascular Research
Study title: The investigation into the dynamics of neutrophil trafficking and function within the lymphatic system during the development of arthritis by multi-photon confocal microscopy

  • Award: £9,912 Consumables

Rheumatoid Arthritis (RA) is a disease that occurs because certain white blood cells (named
lymphocytes), mistake specific structures of the joint as foreign entities. This aberrant immune response leads to irreversible degradation of bones and cartilages contributing to a loss of motility and overall poor quality of life. How these cells are activated to induce this abnormal response is still unclear; and to date there is an unmet need to block specific immune cell functions without the off-target side effects of current therapies. Recently, we have found that during arthritis, neutrophils (another sub-population of immune cells) are present in the lymphatic ganglions where they exhibit a unique characteristic of cells capable of stimulating T-lymphocytes. The aim of this project is to define the exact timing and molecules involved in neutrophil/T-lymphocyte interactions by using a validated animal model of arthritis that recapitulates human RA and by developing a new cutting-edge microscope technique to analyse this new role for neutrophils. This study will therefore enhance our understanding of the cascade of events leading to RA development by demonstrating the control of T-cell activities by neutrophils and will highlight novel therapeutic approaches for the treatment of the cause of this illness.

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