Novel protein interactions in protein kinase D regulation and functions in the heart

Heart failure is a disease that occurs as a result of other cardiovascular diseases (such as a heart attack or uncontrolled high blood pressure) and affects almost a million people in the UK. The severity of the disease and the need for new treatments are reflected by the fact that nearly 40% of people who are diagnosed with heart failure die within a year (a rate of death which is higher than that associated with most cancers), despite receiving treatment with the available drugs. Two cardinal features of heart failure are a change in the shape of the heart, which becomes enlarged, and a compromised ability of the heart to perform its normal pump function. This project will investigate a protein that is found in the heart, called protein kinase D (PKD), which is suspected to contribute to both the shape change and the depressed pump function, focusing on how PKD interacts with other proteins to bring about its effects. We hope that this work will reveal new avenues of investigation towards the development of more effective treatments for heart failure.

Protein kinase D (PKD) is a serine/threonine kinase whose functions in the cardiovascular system have only recently begun to emerge. In particular, there is now good evidence that PKD activity plays critical roles in the regulation of myocardial contraction (through its effects on myofilament calcium sensitivity) and hypertrophy/remodelling (through its effects on the nuclear localization of histone deacetylases), two processes that have direct relevance to the pathogenesis of heart failure. In this project, we will build on our recent observations that PKD interacts with the cardiac-restricted, four-and-a-half LIM-only domain protein FHL2, in a manner that is regulated by PKD?s activation status. Through a series of complementary experiments, we will test the principal hypothesis that FHL2 is a novel interaction partner for activated PKD and that this interaction regulates one or more of PKD?s emerging myocardial functions. We anticipate that this work will improve understanding of the molecular mechanisms that regulate myocardial contraction and hypertrophy. This is likely to stimulate further investigation to substantiate the in vivo significance of the PKD-FHL2 interaction, with a longer-term view to developing new therapies for heart failure.