Dr James O’Kelly
Institution: University of Edinburgh
Title: Single cell definition of the mechanistic role of kynurenine monooxygenase at the innate immune interface in acute pancreatitis
Project Start Date: 7 August 2019
Completion Date: 6 August 2022
Acute pancreatitis is a disease where the pancreas gland becomes inflamed and damaged, normally caused by excess alcohol consumption or gallstones. It is a common cause for emergency surgical admission to hospital, and when severe will kill 1 in 5 patients affected.
Acute pancreatitis not only damages the pancreas gland, but can inappropriately activate inflammation in other organs, most importantly the liver, lung and kidneys. The body’s own immune system damages and destroys these organs. This can make patients extremely unwell, it can kill them, and if they do recover will shorten their life as a result.
Our research team has discovered that this process involves a part of metabolism called KMO. In the body KMO produces a chemical called 3HK which directly damages organs. We also have evidence that 3HK prepares the body to launch an inflammatory reaction. We think that it may act on special immune cells that are essential for how the body controls inflammation.
I want to do this research to discover how 3HK directly activates the immune system in acute pancreatitis. I think it is especially important to discover how 3HK affects the immune cells that control inflammation, and I want to find out how 3HK alters the way genes in our immune cells are controlled.
I am going to do a number of experiments in the laboratory, then I will see if whatever I discover in the laboratory is also happening in patients with acute pancreatitis. First, I will add 3HK to specially-designed cells to discover how and when inflammatory processes are switched on and off. We will then see how 3HK and KMO changes the number and type of immune cells in organs as they prepare to launch an inflammatory reaction in acute pancreatitis, using laboratory models. When we have mapped that out, we will see whether equivalent processes happen in human patients with acute pancreatitis.
I am doing this scientific research in order to discover how inflammation caused by acute pancreatitis is regulated by the body’s immune system, and to find out how new medicines that are being developed for acute pancreatitis work, at the molecular level. This will help us to make better new medicines, improve health, and save lives in acute pancreatitis.