BJA/RCoA PhD Studentship
The successful applicants for the BJA / RCoA PhD Studentship were:
Principal Applicant
Prof Jaideep Pandit
Consultant Anaesthetist, Nuffield Department of Anaesthetics & Associate Professor, Nuffield Department of Clinical Neurosciences
Title
Can the depressive effect of anaesthetics on hypoxic ventilatory responses be explained by action on background potassium channels in the carotid body?
Amount
£74,361
Scientific Abstract
Anaesthetics depress human ventilatory hypoxic responses (VHR) with a specific order of potency (halothane>isoflurane>sevoflurane). Although we know how the carotid body may detect hypoxia, little is known about mechanisms of anaesthetic depression. Our earlier investigations identified a specific O2-sensitive (TASKlike two-pore domain) background K+ (KB) channel, also sensitive to halothane, making it a candidate receptor for the anaesthetic effect. Recently we reported the novel finding that anaesthetics directly depress both the glomus cell hypoxic response and the activity of this KB channel, remarkably with the same order of potency as for human VHR.
Measuring intracellular Ca2+ currents using microspectroflurimetry and K+ currents using cell-attached patch clamping, we will examine dose-response relationships for the interaction of common agents with the KB channels and whether volatile anaesthetics when used in combination demonstrate antagonism (vs additivity) in their effect on KB channels. We will also examine whether intravenous agents display similar characteristics to the volatiles, and we will use mouse knockouts for relevant KB channels to help identify the main channel subtype involved in anaesthetic (and hypoxia) sensing.
Our approach will not only help unravel key molecular mechanisms but also a finding of drug antagonism could challenge a fundamental paradigm in anaesthetic science.
Final report from Prof J Pandit & Dr N Huskens (13 KB)
First Year Progress Report from Prof J Pandit & Dr N Huskens (254 KB)
Please see the NIAA's position statement on the use of animals in medical research.
Principal Applicant
Prof Fang Gao Smith and Dr Jaimin Patel
Professor in Anaesthesia, Critical Care and Pain, University of Birmingham
Title
Neutrophil Dysfunction in Sepsis and its Modification by Statin Therapy
Amount
£66,990
Scientific Abstract
Sepsis remains a common reason for hospitalisation and is the commonest reason for intensive care units admissions. Despite public health initiatives and improvements in sepsis management, the incidence of sepsis continues to increase with unchanged mortality. Although there are many risk factors, sepsis increases in incidence with age and age is a predictor of mortality.
The aim of this research is to quantify the dysfunction that sepsis induces upon neutrophil function. Using state of the art assays and imaging techniques we will assess neutrophil function by analysing directed chemotaxis, reactive oxygen species production and neutrophil extracellular trap formation. By treating neutrophils in-vitro with simvastatin and with plasma from sepsis patients treated with Atorvastatin or placebo we aim to discover whether statins can improve neutrophil function thus overcoming their dysfunctional state.
The results from this study will determine the mechanistic justification for statin therapy as a treatment of sepsis. By looking at the differences in neutrophil function between young and old patients with sepsis and the potential differential effects of statins in these patients, this research will provide novel observational data and translational data about the differential effects of statins that may influence future clinical trial design in patients with sepsis.
First Year Progress Report from Dr J Patel (87 KB)
Final report from Dr J Patel (21 KB)
Principal Applicant
Dr Michael Wilson
Lecturer in Physiology, Imperial College London
Title
Mechanisms of alveolar macrophage activation during ventilator-induced lung injury
Amount
£73,755
Scientific Abstract
Acute lung injury remains an important cause of patient morbidity and mortality within the Intensive Care Unit. Development of ventilator-induced lung injury (VILI) is a crucial determinant of patient survival. It is generally felt that interference with inflammatory pathways is the area most likely to provide therapeutic breakthroughs for VILI. However, this may prove dangerous if immunosuppression leaves the patient at increased risk of infection. One way to avoid such adverse consequences is to identify VILI-specific processes. We have taken the approach of studying the initial 'triggering' processes by which lung stretch stimulates alveolar macrophages (the primary immune cell within the lung), which remains a fundamental unanswered question.
We found that alveolar macrophages are very rapidly activated (5 minutes) by excessive lung stretch in vivo. We propose 2 potential mechanisms for this, which this project is designed to evaluate: 1) rapidly acting soluble mediators secreted from epithelial cells, or 2) contact dependent sensing of epithelial cell deformation by macrophages (our preferred hypothesis). If our primary hypothesis is correct, blockade of macrophageepithelial contact could specifically attenuate the macrophage response to stretch, leaving their ability to respond to infection intact. Such studies may have major impact on the design of therapeutic agents.
Please see the NIAA's position statement on the use of animals in medical research.
Click here to access an article on this project published in Am J Physiol Lung Cell Mol Physiol.2015 May 1: 308 (9): L912 - L921
