Consultant in Acute Medicine & Toxicology
My overall objective is to improve the diagnosis and management of acute medical emergencies by understanding the role and clinical utility of circulating microRNAs. Less than 10 years ago their existence in the circulation was unknown – now microRNAs are recognized to provide a huge reservoir for disease biomarker discovery and a mechanism for signalling between cells that is amenable to therapeutic intervention. My research combines knowledge enhancement with a clear translational pathway that aims to improve health and develop diagnostic and therapeutic products with Scottish, UK and worldwide commercial partners.
We focus specifically on microRNA biomarkers in drug toxicity, which has great importance to both clinical patient care and commercial drug development. Paracetamol (acetaminophen) overdose is one of the most common reasons for emergency hospital attendance and the leading cause of acute liver failure in the Western world. Annually in the UK, paracetamol overdose results in approximately 100,000 Emergency Department presentations and 50,000 acute hospital admissions and is the direct cause of death in around 150 people. We have developed markers that promise to transform the clinical care of this large patient group. Our biomarkers allow early exclusion of liver injury and facilitate prompt identification of injury that will progress despite current treatment. Improved identification of drug-induced liver injury is also of great importance to the pharmaceutical industry in the UK and worldwide. To drive forward our research I have partnered with pharma to translate my academic research into commercial benefit and safer medicines for the public.
In parallel with this biomarker program, we have developed a new shorter and safer treatment protocol for paracetamol overdose that is now being used in Edinburgh, with a plan for roll out across the UK. This promises to free up an estimated 20,000 UK acute hospital bed-days/year, clear evidence of impact ahead of REF2020.
My research group has established a portfolio of pre-clinical models (cell, zebrafish and rodent) that explore the role of microRNAs in toxicology and in cell-to-cell signaling. For example, we have recently developed a new zebrafish model of liver toxicity and performed RNAseq on small and mRNA fractions to identify novel disease pathways. Urine contains extra-cellular vesicles enriched with microRNA that are called exosomes. They are released from the cells that line the glomerulus and kidney tubules. This allows us to use the kidney as a model organ to study exosome mediated signaling in health and disease, in vitro and in vivo
People who develop an Acute Kidney Injury (AKI) often have a poor prognosis and many go on to develop chronic kidney disease (CKD). The recognition that AKI and CKD are linked is recent and the molecular pathways that control the transition from acute injury to chronic disease are not well defined. Currently there are no specific treatments that reduce the risk of progressing to CKD after AKI.
Preliminary investigations (not yet published) suggest that AKI causes sustained activation of the endothelin (ET) system to the long-term detriment of renal and systemic haemodynamic function. These pilot data form the basis of our project that seeks to determine whether the ET system is active in patients with AKI and, thus, represents a potential target for therapeutic intervention.
KRAKIL aims to recruit altogether 100 patients from across the emergency department, acute medical unit and inpatient wards at the Royal Infirmary. 50 of which with AKI’s and 50 matched controls with normal kidney function. We will monitor their bloods and urine for 90 days and compare the data from between the two groups.
The study with PP100-01 in combination with NAC is designed to determine safety and tolerability of PP100-01 when co-administered with NAC as compared to the 12-hr NAC treatment regime for patients that come to the hospital after an overdose of paracetamol/acetaminophen.
A Randomised Open Label Exploratory, Safety and Tolerability Study with PP100-01 in Patients Treated with the 12-hour Regimen of N-Acetylcysteine for Paracetamol/Acetaminophen Overdose