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Young Investigator Awardees

Professor Dear completed a PhD in Pharmacology at University College London before finishing his medical training at Oxford University. After junior medical jobs in Oxford and London, Professor Dear spent 2 years as a visiting research fellow at the National Institutes of Health, Bethesda, USA. Since 2005, Professor Dear has been at the University of Edinburgh. In 2012, he was awarded an NHS Research Scotland (NRS) Career Research Fellowship and in 2017 he was awarded the Grahame-Smith Prize for Excellence in Clinical Pharmacology. In 2020 Professor Dear was promoted to a personal chair in Clinical Pharmacology.

Professor James Dear

Project Summary

Acute liver failure (ALF) has no effective treatment other than liver transplantation, which has limited use because of its associated morbidity/mortality, expense and the scarcity of donor livers. In the Western world, paracetamol (acetaminophen) overdose (POD) is the commonest cause of ALF (around 100,000 POD/year in UK). There are at least 1000 POD-ALF cases treated in liver transplant centres in the US and EU (mostly UK) each year. Mortality in this group is around 30-35%, with about 30% receiving a liver transplant. The only treatment for POD is acetylcysteine (NAC), which is only fully effective if started soon after overdose (within 8h). There is no treatment for non-POD ALF. When the liver is injured, renal function is crucial in determining patient outcome. We proposed that the microRNA species, miR-122, released from the injured liver regulates renal function.

Findings

Kidney cells internalise microRNA with a subsequent change in gene expression. Circulating microRNAs increase substantially when released from an injured organ, such as following drug-induced liver injury (DILI). We explored whether functional liver-derived microRNA is transferred to the kidney. When liver microRNA was depleted in a mouse model there was a fall in miR-122 (hepatocyte-enriched) in the kidney.  Conversely, following DILI there was increased liver-derived miR-122 in kidney tubular cells. Liver-derived microRNA regulated kidney cytochrome P450 2E1 and inhibited toxic injury. This signalling pathway is potentially active in humans – urinary miR-122 was increased with DILI. These findings demonstrate that functional liver microRNA is transferred into kidney tubular cells to regulate gene expression, a signalling mechanism increased by drug toxicity. This microRNA already represents a drug target – miravirsen, a locked nucleic acid-modified DNA antisense oligonucleotide which specifically binds miR-122 – has demonstrated efficacy in a clinical trial to treat hepatitis C. Medicines which target miR-122 may also be effective treatments to prevent renal failure in patients with liver disease.

Grant Schemes