BJA/RCoA Project Grant
The successful applicants for the BJA / RCoA Project Grant were:
Principal Applicant
Prof Tim Hales
Director of the Institute of Academic Anaesthesia, University of Dundee.
Title
Preclinical identification of local anaesthetics that target colon cancer cells
Amount
£63,462
Scientific Abstract
Several studies suggest that the general anaesthesia (GA) and opioid sparing effects of regional nerve block during tumour excision reduce cancer recurrence. GA and opioids inhibit immune function; a reduced requirement may contribute to the benefit of nerve block. In addition, in vitro studies suggest that local anaesthetics (LAs) may directly suppress the metastatic potential and self-seeding of cancer cells through inhibition of their voltage-activated Na+ channels (VASCs). This raises the possibility of an additional therapeutic benefit of LAs delivered systemically and/or directly onto the tumour during excision. Metastatic breast and colon cancer cells express a neonatal variant of the NaV1.5 VASC not found in normal adult tissue. This project will identify LAs and related compounds that target these VASCs at concentrations that spare cardiac NaV1.5. The neonatal NaV1.5 channel has novel functional properties that may promote inhibition by some LAs. We will screen several LAs to identify those with the highest selectivity for VASCs on colon cancer cells. The potencies of LAs as neonatal NaV1.5 inhibitors will be correlated with their potencies as inhibitors of cell motility and invasion. This preclinical study will be used to guide subsequent clinical trials investigating the benefit of intraperitoneal LA administration during colorectal cancer surgery.
First Year Report from Prof Tim Hales.pdf (578 KB)
Principal Applicant
Dr Simon Lambden
Academic Clinical Fellow in Anaesthesia and Critical Care, University College London
Title
The role of the Nitric Oxide regulatory pathway in critical illness
Amount
£9,000
Scientific Abstract
Dysregulation of Nitric Oxide (NO) production is associated with morbidity and mortality in critical illness. Production of NO is controlled by methylarginine arginine analogues such as N-monomethyl-N-arginine (LNMMA) and Asymmetric N,N-dimethyl-L-arginine (ADMA). These are produced intracellularly by PRMTs and metabolised by NG,NG-dimethylarginine dimethylaminohydrolase (DDAH). Ninety percent of total ADMA is intracellular. NO overproduction in critical illness is largely due to de novo production of inducible NO synthase (NOS). Studies have associated the plasma portion of ADMA with poor outcomes in critical care although impaired clearance associated with organ dysfunction may complicate this. Dynamic changes that occur, or the role of the intracellular ADMA portion during the early days of critical illness, have not been examined. We will employ established septic animal models and perform a prospective observational study in critical care patients to (i) evaluate the temporal relationship between monocyte and extracellular ADMA over the course of sepsis, (ii) correlate monocyte and plasma ADMA with expression and activity of the regulatory enzyme DDAH2, NOS and NO levels (iii) compare these components of the NOS regulatory pathway with the clinical and immune phenotype.
Please see the NIAA's position statement on the use of animals in medical research.
Principal Applicant
Prof Andrew Rice
Professor of Pain Research, Imperial College London
Title
The role of HIV gp120-driven macrophage-sensory neuronal interactions in the pathogenesis of HIV-associated polyneuropathy and neuropathic pain
Amount
£64,592
Scientific Abstract
HIV-associated sensory neuropathy (HIV-SN), and the associated neuropathic pain, is the most frequent neurological complication of HIV disease seen in the current era of successful antiretroviral therapy. Our previous research indicates that the HIV envelope glycoprotein gp120 is likely to be the key molecule in the pathogenesis of HIV-SN. Gp120 binds to macrophage-expressed CCR5 receptors, causing the release of proinflammatory mediators that are neurotoxic to sensory neurons. Current evidence indicates that dorsal root ganglion (DRG) is likely to be the primary site of this macrophage sensory neuron interaction. This proposal aims to document the time course of this interaction and test our hypothesis that this pathology is initiated at an early stage of infection. Using an animal model we will: 1)investigate changes in DRGs following SIV-infection at different stages of infection, document axonal "die back" in skin samples, and then establish correlation between the macrophage-associated events in DRG and epidermal innervation loss, 2) explore changes in gene expression of 92 cytokines and chemokines in DRGs following SIV-infection with the aim to identify novel therapeutic targets, 3) explore the strategy of targeting the upstream interaction of gp120 with macrophages-expressed CCR5 using CCR5 antagonist Maraviroc which is already clinically available.
Please see the NIAA's position statement on the use of animals in medical research.
