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BJA/RCoA Basic Science Research Fellowship: 2014

Chair's Report

Six applications were received for the 2014 BJA/RCoA Basic Science Research Fellowship Grant. Independent external review and scoring against set criteria took place in the weeks prior to the panel meeting on 14 February 2014, at the Royal College of Anaesthetists, Churchill House. Panel members were:

Professor Hugh Hemmings, Chair, Weill Cornell Medical College, New York
Professor Anthony Absalom, University Medical Center Groningen, The Netherlands
Professor Helen Galley, University of Aberdeen
Professor Graeme Henderson, University of Bristol
Mr David Hepworth, Patient Liaison Group Representative, RCoA
Professor Dave Lambert, University of Leicester
Dr Iain Moppett, University of Nottingham

In attendance: Miss Clare Bunnell, NIAA Administrator

Written evaluations and scores were provided by members of the panel along with expert reviewers for each proposal. Following the presentation of each grant by a member of the panels and detailed discussion by the panel of each application, it was agreed that the strongest proposals were from Dr Gareth Ackland (University College London) and Dr. Daqing Ma (Imperial College London). This was consistent with the rankings based on the scores from the external reviewers.

I am very grateful to the independent reviewers, panel members and administrators for their participation in this important process. In particular, I would like to thank Mr David Hepworth (Patient Liaison Group) and Professor Graeme Henderson who generously gave up their time. The quality of the applications was extremely high as reflected in the praise received from our external advisors. The abstracts from the two successful proposals are shown below. On behalf of the review committee, the NIAA and the RCoA, I wish grant recipients success in their exciting and important projects.

Professor Hugh Hemmings, Chair

 Minutes of the BJA & RCoA Basic Science Research Fellowship Committee (187 KB)


Funded applications

Principal Applicant
Dr Gareth Ackland

Title
Parasympathetic modulation of perioperative myocardial injury

Amount
£250,000 over four years

Scientific Abstract
Perioperative myocardial injury (PMI) is a major cause of postoperative morbidity and mortality. PMI occurs early, yet is usually clinically asymptomatic. The conduct of anaesthesia probably contributes to PMI, although clinical and experimental investigations are limited. Understanding PMI mechanisms, and thus defining new therapeutic avenues, is an urgent priority. Preservation, or restoration, of vagal activity is cardioprotective. Parasympathetic neural activity is dramatically reduced following major surgery and trauma. This neural cardioprotection may be exerted either directly at the level of the cardiomyocyte or, indirectly, by modulating immune cells that may potently modulate myocardial injury through the release of pro-coagulant and inflammatory mediators. At the molecular level, the interaction of parasympathetic neurotransmitters with specific signalling pathways will enable downstream molecular targets that are cardioprotective to be elucidated. The translational approach of exploring cardioprotective neural control mechanisms using neuro- and optogenetically modified laboratory models, plus human experimental and perioperative paradigms, affords an unprecedented opportunity to enhance understanding of PMI.

Lay Abstract
Injury to the heart is commonplace during major surgery. This dramatically increases the risk of postoperative death and other complications, and delays recovery. The exact reasons why heart damage occurs during or shortly after surgery remain unclear, but are likely to be heavily influenced by anaesthesia. A better understanding of these mechanisms is necessary to develop new strategies to protect the heart and improve outcomes.

The heart and other organs in the body are protected by specialized nerves that constantly monitor our health. These nerves feedback signals to the brain that, in response to organ injury, can emit signals that alter hormone levels and modify inflammation. The vagus nerve is one such protective nerve that is particularly effective at protecting the heart. However, the vagus nerve's protective effect essentially switches off during acute stressful situations such as surgery and anaesthesia. This may then result in damage to the heart tissue, resulting in postoperative complications.

I will assess the effect of switching vagus nerve function on and off in laboratory models of clinically relevant heart injury to reveal which mechanisms are important in protecting the heart during surgery. The genetic code for these mechanisms is leaked into the blood by damaged heart tissue. If the same code can be identified in patients, this will allow rapid advances in our understanding of why heart injury occurs following surgery. By looking for the same genetic code that is leaked into the bloodstream from laboratory models in patients who suffer from heart injury postoperatively, new targets for treatments and medical management can be identified.



Principal Applicant
Dr Daqing Ma

Title
Novel preservative strategy in enhancing marginal kidney donor pool

Amount
£187,136 over three years

Scientific Abstract

Background:
Kidney transplantation is a cost-effective treatment for patients with end-stage renal failure. Despite the demonstrated advantages of transplantation, the full potential of these benefits cannot be obtained due to the severe shortage of donated kidneys. Effective preserving strategies to ameliorate donor kidney graft ischemia injury will serve to both improve graft function after engraftment while also expanding the pool of marginal donor organs. We have shown previously including in a renal transplant setting that noble gas xenon, argon and α2 adrenoceptor agonist, dexmedetomidine (DEX), protect against brain or kidney ischemia reperfusion induced injury. Using a rat hypothermic machine perfusion model, we aim to explore whether exposing xenon, argon and DEX alone or in combinations of xenon or argon with DEX to ex vivo renal grafts from brain death or cardiac arrest donors prior to engraftment can prevent kidney graft injury histologically and functionally. If successful, we will translate this approach into clinical practice leading to a considerable increase in viable organ availability.

Aims:
Using our established rodent renal machine perfusion system, our preliminary data (see below) indicated that xenon or argon supplemented with or without DEX protected against renal "marginal" graft injury induced by ischemia/reperfusion when administered during ex vivo storage and these treatments remarkably improved renal function. We intend to apply these techniques to renal grafts from brain death or cardiac arrest donors to further assess function and survival of renal marginal graft.

We wish to develop these strategies to enhance marginal donor graft use.

Plan of investigation:

  • To analyse the changes of reno-protective protein or inflammatory markers in ex vivo allograft (Fischer to Lewis) from brain death or cardiac arrest donors, through immunoflurecence and western blot. The severity of ischemiareperfusion injury upon grafting, after being exposed to xenon or argon, supplemented with or without DEX, will be also assessed histologically.
  • To assess the early functional recovery in Fischer to Lewis allografts from brain death or cardiac arrest donors, after being exposed to above mentioned therapeutants in ex vivo stage.
  • To evaluate the severity of ischemia-reperfusion injury and the long-term survival in Fischer to Lewis allografts from brain death or cardiac arrest donors after being exposed to above mentioned therapeutant in ex vivo stage.

Potential impacts:
More than 9,000 people in the UK need an organ transplant to save or improve the quality of their lives; most are awaiting kidneys. In 2007, 6,200 patients were on the waiting list for kidney transplantation. Donor organs are therefore highly precious resources, and any intervention that reduces graft failure would be of enormous benefit. If the proposed therapeutants protect against ischaemia reperfusion injury (IRI) and "rescue" marginal grafts, the survival and function of the transplanted marginal renal grafts will thereby be improved. While these studies are confined to renal transplantation, the clinical utility of these strategies could be extended to all organ transplantation in which ischaemic/reperfusion injury impairs graft function.

Lay Abstract

Background
Kidney transplantation is the optimal treatment for patients with end-stage renal failure and provides the best clinical outcomes, better quality of life and cost savings when compared to other modalities of renal replacement therapy. Currently, there are approximately 7,000 patients on the waiting list for a kidney transplant. Sadly, around 300 patients die each year while waiting for a kidney graft (Kidney Research UK). Clearly, despite the demonstrated advantages of transplantation, the full potential of these benefits cannot be obtained due to the severe shortage of donated kidneys. Efforts are underway to expand the potential donor pool including use of 'Extended Criteria' (EC) or 'marginal' kidney donors. However, grafts from these donors are often damaged by patient co-morbidities, ischaemia and stress responses.

These would explain the apparent synergy noted clinically between the effects of delayed renal graft function and acute rejection episodes, leading to increasing deterioration and failure of the graft over time. Novel therapeutic approaches designed to "normalise" the affected graft during the preserving stage, i.e. before engraftment, are urgently required.

Aims:
1. To investigate whether the novel strategies applied before engraftment attenuate ischemia-reperfusion injury in marginal donor renal grafts
2. To further assess whether these novel strategies prolong the long-term survival in marginal donor grafts.

Plan of investigation:
1. To analyse the expression profile of protective molecules and to assess renal cell survival or death after being treated with these novel strategies at the preserving stage
2. To evaluate the functional recovery in the marginal renal grafts after being treated with these novel strategies at the preserving stage
3. To explore the long-term survival of marginal renal grafts after being exposed with these novel strategies after the preserving stage.

Potential impacts:
We proposed to investigate the effects of exposing the novel strategies to renal grafts from marginal donation at the preserving stage. We wish to obtain a definite answer at the pre-clinical study level whether the proposed strategies are protective for renal marginal grafts, providing data which could very likely lead to clinical trials and ultimately change our practice to benefit our transplant patients and, eventually, lead to expansion of the available renal graft donor pool and improvement of renal graft survival.

Please see the NIAA's position statement on the use of animals in medical research.