IDENTIFYING CARDIAC SUBSTRATES OF p38alpha MITOGEN-ACTIVATED PROTEIN KINASE

在心脏应激期间，一种被称为p38α丝裂原激活蛋白激酶(P38)的酶变得活跃。P38酶的目的是通过向蛋白质中添加磷酸盐来改变蛋白质的功能。在许多情况下，这有助于细胞对压力做出反应。然而，很明显，在某些情况下，p38的激活会加重损伤。激活p38既有好的结果，也有坏的结果，这一事实可能解释了为什么抑制p38的临床试验尚未显示出益处。这个项目的目的是在p38内产生突变，从而微妙地改变其酶活性。这些突变意味着有可能追踪到p38添加了磷酸的蛋白质。这将使我们能够识别p38修饰的单个蛋白质，并找出哪些变化有助于细胞对压力做出反应，哪些变化加剧损伤。最终，这些知识可能会帮助细胞对压力做出反应，例如冠状动脉血栓形成后的心肌梗死，从而实现精细化的治疗。

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.