Preventing TAB1-mediated p38 activation during myocardial infarction

Lead Research Organisation: King's College London
Department Name: Cardiovascular

Abstract

During myocardial infarction an enzyme called p38 becomes activated and worsens the injury suffered by the heart. Although p38 can be inhibited with drugs, and this leads to reduced heart injury, these drugs have caused serious side effects in early clinical trials. This is probably because p38 is a very important enzyme throughout the body. The purpose of this grant is to find a way of inhibiting p38 during myocardial infarction by interfering with the way it becomes activated. The reason why this is attractive is that the activation mechanism during myocardial infarction is very unusual in that it requires p38 to bind another protein called TAB1. Thus interfering with this mechanism should not inhibit p38 activation under other circumstances.

Technical Summary

The activation of 38alpha mitogen-activated protein kinase (p38alpha) during myocardial ischaemia aggravates lethal injury. However, under other circumstances activation of this kinase can protect the heart. During myocardial ischaemia the activation of p38alpha occurs through an unusual mechanism involving a scaffold protein known as TAB1 that causes p38alpha to autophosphorylate its activation loop.
The purpose of this project is to characterise the molecular basis of the interaction between p38alpha and TAB1 in order to disrupt it. The interface residues on p38alpha and TAB1 will be mapped by NMR chemical shift perturbation and cross-saturation transfer techniques and then confirmed by mutagenesis analysis. The TAB1-induced 3 dimensional rearrangement of p38alpha will also be analysed. This information will be used to design peptides and small molecules to disrupt the TAB1-p38alpha interaction in physiological systems. Such reagents maybe of considerable value since they could prevent the detrimental, but not the beneficial, activation of p38 and thereby perhaps overcome the toxicity seen to date in clinical trials of inhibitors of p38 catalytic activity.
 
Description Discovery Partnership With Academia 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Provision of knowledge, X-ray structures, recombinant proteins and orthogonal screens
Collaborator Contribution Provision of novel high through put screen
Impact None as yet
Start Year 2014
 
Description Hosting 4 work experience students each for one week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact Formal feedback good to excellent all domains

Schools requested repeat placements for next year
Year(s) Of Engagement Activity 2012,2013