Molecular Pathogenetic Mechanisms of Heart Failure - Dissecting GRK Function in The Heart

Heart failure, the final outcome of many cardiovascular disorders, is a major cause of morbidity and mortality in the Western Hemisphere. Indeed, the incidence and prevalence of heart failure in the Western Hemisphere are increasing due to altered demogra phics with increased proportion of elderly, as well as increased survival of myocardial infarction. Despite implementation of several new treatment modalities during the last 20 years, heart failure is still a progressive and ominous disease, indicating t hat important pathogenetic mechanisms remain unmodified by the most current treatment. Development of heart failure is characterized by several alterations of myocardial structure including dilatation of the ventricular cavities, cardiac myocyte hypertrop hy and fibrosis. These important structural alterations of the heart, often referred to as cardiac remodeling, have recently been emphasized in the new recommendations of the American College of Cardiology/American Heart Association Task Force for the eva luation and management of chronic heart failure in the adult. These new approaches to the classification of heart failure, which are meant to complement the New York Heart Association (NYHA) functional classification, stratifies patients according to risk factors for developing heart failure, and to the absence or presence of structural alterations of the heart. Although, recent research has provided substantial new insights into the mechanisms of myocardial hypertrophy and fibrosis, many of the nodal poi nts that orchestrate these structural alterations still remain to be identified in order to develop new and more effective therapeutic modalities. In this respect, the aim of the present research proposal is to provide novel insights into the G protein-co upled receptor kinases (GRK), i.e. a family of kinases that are important proximal modulators of many receptor-controlled signal transduction pathways involved in regulation of myocardial function and growth.