IDENTIFYING CARDIAC SUBSTRATES OF p38alpha MITOGEN-ACTIVATED PROTEIN KINASE

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During cardiac stress an enzyme known as p38alpha mitogen-activated protein kinase (p38) becomes active. The purpose of the p38 enzyme is to alter the function of proteins by adding phosphate to them. In many cases this helps cells respond to stress. However it is clear that under some circumstances p38 activation worsens injury. The fact that activation of p38 can have both good and bad consequences may explain why clinical trials of p38 inhibition have not yet shown benefit. The purpose of this project is to create mutations within p38 that subtly alter its enzyme activity. These mutations mean that it is possible to trace the proteins to which p38 has added a phosphate. This will allow us to identify the individual proteins modified by p38 and work out which changes help cells respond to stress and which worsen injury. Ultimately this knowledge may enable refined therapies that help cells respond to stresses such as the myocardial infarction that follows coronary artery thrombosis.