Maladaptive Kinase Signaling and Protein-Protein Interactions in Cardiac Diseases

Abstract

The incidence of cardiac diseases has been on the rise in the past decades and both academic and industrial institutions are still heavily involved in the development of new drugs. Discovery of suitable targets and highly efficient compounds relies on a better understanding of the cellular mechanisms underlying the disease. The basis of all cellular mechanisms is proteins, which, are also known to be the most basic functional units of life. This implies that studying proteins in more depth and discovering new proteins will tremendously help in not only in having a better understanding of cardiovascular disease mechanisms but also help in drug development. This thesis focuses on studying proteins during cardiac physiology and pathophysiology. Using advanced biological and chemical techniques we have discovered a set of proteins that we believe are members of the cardiac intercalated disc the region that is responsible for electrical conduction in the heart. This set of proteins will help in revealing the structure of this organelle to a large extent and also help in understanding mechanisms of diseases associated with it such as arrhythmogenic cardiomyopathy. The second part of this thesis deals with studying a specific family of proteins called the kinase of family of proteins. We have studied two members of this family, PKA and CaMKII. Both these enzymes are involved in the adrenergic drive of the heart, which is disturbed when the heart is a diseased state. We dissect molecular mechanisms that underlie the maladaptive behavior of these enzymes and discuss the importance of a balanced environment that needs to be maintained between these two important players in the heart. The research performed in this thesis highlights the need for the discovery of the complete cardiac proteome and illustrates how this can be achieved by the use of advanced biological and chemical techniques. At the same time it also shows the versatile functional nature of proteins by shedding light on how two functionally similar proteins behave differently under similar conditions. This is due to an organizational change in the molecular mechanisms leading to their final activation, and is telling us that in order to achieve more specific drug targets the knowledge of specific molecular mechanisms underlying the activity of these enzymes is crucially important.