Grant: Project Grant

Patients surviving a heart attack or those with hypertension develop chronic heart disease. These patients make too much collagen in their heart muscle, wherein non-muscle cells called myofibroblasts secrete excessive collagens, which stiffens the heart. Most of the "glue" (extracellular matrix) between muscle cells in healthy hearts is made of tough collagen proteins. Too much collagen leads to cardiac fibrosis which results in weak muscle contraction and relaxation. Despite this, there is currently no treatment for cardiac fibrosis, nor are there any specific cardiac drugs approved to fix cardiac fibrosis. In recent years, we have found a new protein called Ski. Ski turns off this over-deposition of matrix, in diseased heart cells. Further, we have made progress of how Ski actually achieves this positive change. We are now poised to extend our understanding of how Ski corrects cardiac fibrosis. We discovered that Ski is able to deactivate cells that cause fibrosis, and this is associated with normal control of the extracellular matrix; but our also work shows that Ski somehow is redirected and lost in heart failure. So, we hypothesize that loss of Ski's function in sick hearts may contribute to cardiac fibrosis and speed up the onset of heart disease - our experiments will test this hypothesis directly in mice wherein we specifically turn off Ski in cells making extracellular matrix. Finally we hypothesize that Ski turns off the function of special proteins that normally promote fibrosis in sick hearts. Experiments designed to answer this will show the mechanism of Ski's beneficial effects. Thus we will tease out and develop our understanding of how Ski protein influences the progression of cardiac fibrosis, and how this work will allow us to design new Ski-based therapies to treat cardiac fibrosis, for the prevention of heart failure.