BJA/RCoA Project Grant
The successful applicants for the BJA / RCoA Project Grant were:
Principal Applicant
Prof Tim Hales
University of Dundee
Title
Improving opioid analgesia by targeting beta-arrestin2 signalling
Amount
£65,000
Scientific Abstract
Opioids have been used as analgesics for thousands of years and remain a mainstay for pain management despite their problematic side effect profile, which includes tolerance, physical/psychological dependence, constipation, and respiratory depression. Despite these drawbacks opioids including the prototypical agent morphine remain widely used in the treatment of severe pain. The phenomenon of analgesic tolerance is the biggest drawback of this class of drugs due to the resulting requirement for escalating opioid doses increasing the likelihood of the other side effects. Recent research has implicated the scaffold/signalling protein beta-arrestin2 in the negative effects of opioids. Deletion of the beta-arrestin2 gene from mice abolishes analgesic tolerance and initiates persistent opioid receptor mediated analgesia. This occurs with no apparent disruption to opioid receptor mediated reward. The ubiquitous protein kinase c-Src, a target for several anti-cancer drugs including dasatinib, is a signalling partner of beta-arrestin2, which may mediate negative effects of opioid analgesic drugs and contribute to tolerance. The goal of this project is to determine whether inhibition of c-Src achieves long lasting analgesia without dependence. A positive result may change clinical practice leading to the use of dasatinib and other c-Src inhibitors to produce sustained analgesia in cancer patients.
Please see the NIAA's position statement on the use of animals in medical research.
Principal Applicant
Surg Cdr Sam Hutchings
King's College Hospital
Title
MICROSHOCK: An observational pilot study of the effects of haemorrhagic shock and resuscitation on the microcirculation.
Amount
£23,271
Scientific Abstract
Haemorrhagic shock is the leading cause of preventable death following traumatic injury. Despite successful resuscitation some survivors go on to develop an exaggerated inflammatory response and subsequent organ dysfunction. We hypothesise that early disruption of the microcirculation is an important cause of this morbidity. The MICROSHOCK study is an observational pilot study involving critically ill adult trauma patients who receive blood products during initial resuscitation. The primary objective of this study is to examine the relationship between early microcirculatory failure and late organ dysfunction. The secondary aim is to elucidate the causes of microcirculatory dysfunction in this patient cohort. Clinical assessment of the microcirculation will be carried out using sequential sublingual side stream dark field microscopy. Correlation with global haemodynamics will be made using focused trans thoracic echocardiography and oesophageal doppler. Assessment of the mechanisms of microcirculatory dysfunction will involve studying markers of endothelial and glycocalyx integrity (endothelium derived microparticles, syndecan-1), assessment of granulocyte function (VCAM-1, ICAM-1, IL 6) and erythrocyte fragility (free Hb) and a functional assessment of inducible nitric oxide synthase. Those elements that show most promise as future clinical biomarkers of microcirculatory dysfunction will be developed in larger scale observational and eventually interventional studies.
Principal Applicant
Dr Brijesh Patel
Imperial College London
Title
Death receptor signalling in acute respiratory distress syndrome
Amount
£64,955
Scientific Abstract
The acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality and has no therapies except for ventilatory support. The alveolar epithelium is critical to barrier function and clearance of fluid from the alveolus. We have recently found that TNF receptor 1 induced death signalling triggers epithelial dysfunction and alveolar oedema formation during early ARDS induced by acid aspiration in mice. Significantly, there was no cell death at that stage, with only the presence of substantial caspase-8 activation leading to significant physiological dysfunction.
The biological effects of death receptor activation (such as TNF-R1 and Fas) are determined by the extent to which there is activation of complex-1/survival versus complex-2/death signalling. Our objective is to explore the cellular and molecular factors that determine complex-1 or complex-2 signalling in ARDS. We will profile the cell specific survival/death signalling balance in the lung and explore the mechanisms leading to Fas activation and propagation of epithelial caspase-induced dysfunction. Thirdly, we will investigate how resolution of inflammation improves epithelial function by potentially modulating survival/death signalling. Finally, we will explore the impact of caspase inhibition on respiratory physiology and cell specific survival/death balance in ARDS.
Please see the NIAA's position statement on the use of animals in medical research.
Principal Applicant
Dr Carole Torsney
The University of Edinburgh
Title
Optimising translational capacity of melatonin administration for chemotherapy induced neuropathic pain
Amount
£65,000
Scientific Abstract
Chemotherapy induced neuropathic pain (CINP) is a common side effect of chemotherapy, which can result in dose reduction, or cessation, with a resultant effect on survival and quality of life. Oxidative stress and mitochondrial damage have been implicated in CINP. Exogenous melatonin and its metabolites have marked antioxidant activity. We have evidence that they can reduce paclitaxel-induced oxidative stress and mitochondrial damage in dorsal root ganglion cells in vitro. Using an in vivo rat model we have also found that melatonin given to rats in drinking water improved mechanical hypersensitivity induced by paclitaxel administration. Melatonin is non-toxic even at high doses and therefore represents a promising novel therapeutic strategy for patients with CINP.
The aim of this proposal is to further establish the translational possibilities of melatonin with a view to undertaking a subsequent clinical trial in patients. We propose to determine circulating levels of melatonin and key metabolites; to characterise the relative analgesic effects of different doses and treatment schedules and to detail these parameters in both male and female animals. We also aim to identify a suitable biomarker of oxidative stress in patients. Collectively, the results of the study will inform a planned clinical trial in the future.
Please see the NIAA's position statement on the use of animals in medical research.
