BJA/RCoA Non-clinical PhD Studentships

University of Oxford

Title
Exploring novel sub-additive (antagonistic) interactions between anaesthetic agents

Amount
£97,284

Scientific Abstract
It is axiomatic that two different general anaesthetics in combination act additively in producing anaesthesia. No infra-additive or antagonistic effects are described. This is traditionally argued to support a 'non-receptor' mechanism of action (e.g., lipid solubility theory) or, now that anaesthetics are known to act on specific ion channels, it is taken to imply that although agents may differ in potency they have similar efficacy. Whilst investigating the effects of anaesthetics on chemoreceptor oxygen sensing we have serendipitously observed infra-additive/ antagonistic effects of combinations of halothane and isoflurane on both hypoxia-induced Ca2+ signaling and TASK potassium-channel activity. Furthermore, in concentration-effect relationships, halothane appeared to have a greater efficacy than isoflurane. In a conventional, competitive binding model, low-efficacy (partial) agonists are predicted to antagonise the effects of high-efficacy agonists. Whilst such interactions are the norm for most drugs they have not hitherto been observed with volatile anaesthetics. This could have profound implications for our understanding of how volatile anaesthetics work at the protein level. Our results to date however have been obtained in complex cells which contain multiple forms of TASK channel. It is therefore imperative that we confirm our observations in simpler preparations containing individual forms of TASK channel.

University of Dundee

Title
Using c-Src inhibitors to improve opioid analgesia

Amount
£87,048

Scientific Abstract
The prevalence of persistent moderate to severe pain is high, affecting 19% of Europeans. While opioids are among the best analgesics for severe pain their prolonged use is compromised by tolerance, which leads to reduced potency and a requirement for escalating doses to maintain adequate pain control. Pain management is also compromised by the major opioid side effects: constipation and respiratory depression. While the beneficial effects of opioids are mediated through inhibitory G proteins, prolonged mu opioid receptor (μ) stimulation recruits β-arrestin2, which participates in μ endocytosis and signalling through kinases including c-Src. Mice that lack β-arrestin2 exhibit negligible morphine tolerance, constipation and respiratory depression. We recently discovered that tolerance is also attenuated by c-Src inhibition raising the intriguing possibility that the kinase may be responsible for the β-arrestin2-dependent detrimental effects of opioids.

The goal of this studentship is to establish whether c-Src inhibitors abolish tolerance, constipation and respiratory depression caused by analgesic opioids. This will be done in mice using c-Src inhibitors including the anti-leukaemia drug, dasatinib. A positive outcome will pave the way for a clinical trial testing dasatinib in conjunction with opioids for the treatment of chronic severe pain.

Chelsea and Westminster Hospital

Title
Necroptosis and sterile inflammation are involved in remote organ injury after kidney engraftment: Implication for consequences following traumatic surgery

Amount
£89,987

Scientific Abstract
Early graft injury from marginal kidney transplantation could induce extra-renal complications. This study aims to investigate the role of necroptosis (regulated necrosis) and DAMP (danger/damage molecular pattern) - driven sterile inflammation in the lungs and small intestines following marginal renal transplant. Using an established rat kidney transplantation model, markers of necroptosis and sterile inflammation will be quantified by immunofluorescence, western blot and ELISA to confirm activation of both pathways in lungs and intestines. Molecular mechanisms of necroptosis-induced sterile inflammation will be studied in vitro, by chemical blockade or genetic knockdown of necroptosis-executing kinases. Specifically, DAMP release and inflammasome activation will be quantified in lung/macrophage and intestinal/macrophage co-cultures following necroptosis induction, and changes in DAMP release and inflammasome activation with chemical inhibition or genetic knockdown would indicate a causal relationship. Furthermore, therapeutic potential of necroptosis inhibition in remote organ injury will be studied in vivo, through chemical blockade or genetic downregulation of necroptosis. Resolution of inflammation and injury in the lungs and small intestines will be assessed by histological examination and physiological function test. Results of the study are expected to decipher mechanisms of necroptosis and sterile inflammation in transplant-associated multi-organ injury, and open up new therapeutic avenues for post-transplant/surgery management.