Grant: Operating Grant

The proposed experimental and modelling studies will result in an improved understanding of the principles and cellular mechanisms which govern the physiological, pharmacological and pathophysiological responses of non-muscle cells (fibroblasts) isolated from the hearts of adult mammals. Fibroblasts are thought to function only as mechanical and metabolic 'support cells' for cardiac cells (myocytes). Myocytes are the heart cells which contract; collectively they produce the heart beat. Our approach will be multidisciplinary, that is it will employ techniques from a number of different scientific disciplines. Cellular electrophysiological methods (patch clamp) will be complemented by simultaneous records of membrane potential using voltage sensitive dyes, and spectrophotometric measurements of changes in intracellular calcium. The planned studies will address a number of fundamental questions: i) What is the electrophysiological or ionic basis of the fibroblast resting potential? (ii) Do myocytes and fibroblasts interact by cell-to-cell current flow (electrotonically) or through chemical messenger systems or both? iii) Do fibroblasts synthesize and secrete biological substances which alter heart contractility? Most of these experiments will be carried out using acutely isolated fibroblasts from the ventricles of adult mouse and rat hearts. However, fibroblasts from human atrium will also be utilized. We will take advantage of genetic information and some aspects of molecular medicine so that, where possible, our data can be related to Clinical Physiology and Pathophysiology. Where appropriate, our findings and data from the literature will be integrated by developing a mathematical model of cardiac fibroblast/myocyte interactions. This model will aid in the design of new experiments and provide a valuable teaching tool for trainees, graduate students and clinical fellows.