Cardiac electrical function, Ca2+ sensitivity and arrhythmogenesis in mice with genetic modifications of Pak1

Heart disease remains the prime killer in the western world. In the UK, heart disease kills 175,000 people every year and 2.6 million people live with debilitating heart conditions. More than 50% of deaths from heart diseases result from cardiac arrhythmias at a total annual national cost of treatment of #~1.6 billion.

The main rationale and motivation of our research is to improve treatment of cardiac rhythm disorders. Current therapies are highly unsatisfactory. Our experiments test a new direction in potential treatment strategies. We have discovered that an enzyme called P21-activated kinase1 (Pak1) is able to chemically modify the elements in heart cells responsible for the rate and rhythm of the heart beat. Our project will take these findings to the next essential level, i.e. understanding the function of Pak1 in intact beating hearts. Our approaches involving enhancing or disabling the function of Pak1 and determining the outcome of these modification on the generation of altered heart rythm mimicking electrical disorders in the human heart. This project is pivotal for understanding of regulatory mechanisms for cardiac electrical and contractile functions and will provide information essential to the development of new treatments for cardiac rhythm disorders.

Cardiac electrical function is highly regulated on a beat to beat basis by multiple extra- and intra-cellular signalling pathways through control of the activity of the ion channels across the membrane of the heart cells. How such regulation is designed to maintain normal cardiac function under broad physiological conditions and how it comes into play in the face of disease conditions are important issues to be addressed. Our recent studies indicate a novel role of P21 activated kinase-1 (Pak1) in regulating cardiac electrical and contractile functions. The proposed project thereby aims to further clarify the mechanisms underlying the critical roles of Pak1 in regulating cardiac electrical function, myofilament Ca2+ sensitivity and ventricular arrhythmogenesis using mice with genetic modifications of Pak1. The physiological consequences of targeted modifications will then be investigated at the cellular, tissue, whole heart and organism levels. Multi-disciplinary approaches including in vivo physiology, mechanics, electrophysiology and molecular biology will be used. The work will shed light on a major area of uncertainty in cardiac regulation and directly lead to new therapeutic strategies directed at human cardiac arrhythmic disease.