Searching for a safer way to treat heart disease

Understanding the interaction between p38alpha mitogen-activated protein kinase and TAB1

Michael S Marber (lead researcher)

King's College London

Start date: 18 May 2015 (Duration 4 years)

The enzyme p38, can be found in every cell in the body. It is part of our response to stress and we cannot live without it. But in a similar way to adrenaline and other stress hormones, p38 becomes very active in some diseases and causes damage. It is particularly active in the hearts of patients with heart failure and ischaemic heart disease. Whilst blocking adrenaline and stress hormones in people with heart disease makes them feel better and live longer, blocking p38 has toxic side effects in the liver, skin and kidneys that outweigh the positive effects in the heart.

For the last 15 years, Professor Michael Marber and his team have been studying p38. They have discovered that the way p38 is activated in the heart when blood flow is restricted is different to the way it is activated in other tissues. They found that p38 rearranges itself after activation, which only takes place when it attaches to a scaffolding protein called TAB1. The team’s work has identified new structural features of p38 that could provide fresh routes to block the enzyme, matching the benefits of current p38 blockers but without the toxic side effects.

The BHF has now awarded them a grant to study these molecules in more detail and work out exactly how TAB1 activates p38. They will work out the structural changes that occur in p38 and how these lead to chemical changes inside heart cells. They also intend to understand when and where in the body TAB1 activates p38. If successful, the team will develop a screening tool to search for new drug molecules to block p38.

Ultimately, the researchers hope their research will lead to a new class of drugs that block p38 in the heart, without the side effects of current drugs.

Project details

Grant amount £698,519
Grant type Special Project
Start Date 18 May 2015
Duration 4 years
Reference SP/14/2/30922
Status In progress

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