Grant: Operating Grant

Congestive heart failure is a major burden to society, in terms of mortality, morbidity and fiscal cost. Our lab carries out research on the heart, with a focus on chronic myocardial ischemia, infarction and cardiac remodeling. The heart contains numerous cell types including myocytes (muscle cells) and fibroblasts (non-muscle cells). Fibroblasts and activated myofibroblasts contribute to cardiac fibrosis after heart attack due to overproduction of collagen. Myofibroblasts show two key features: -they can contract and rearrange the extracellular matrix between normal heart cells and they make much more collagen then the relatively quiet fibroblast. We study cellular and animal models of human cardiac disease. A key cellular protein called Ski acts as a cellular brake to prevent runaway activation of fibroblasts that leads to fibrosis. Ski has associated with reduced collagen synthesis and even removal of myofibroblasts from damaged heart. Thus we believe that Ski plays a key role in slowing fibrosis in injured hearts. Our overall premise is that in the healthy heart there is a balance between pro-fibrotic and anti-fibrotic pathways. After a heart attack, we believe this balance tips towards fibrosis and ultimately to overt cardiac fibrosis and heart failure. At a cellular level, Ski inhibits the ability of R-Smads to function in the nucleus. Our objective is to determine the role of Ski in the progression of heart failure and identify the pathways it controls to regulate fibrosis. Our investigation will show that loss of normal Ski function is a crucial event in the development of cardiac fibrosis and cardiac remodeling following heart attacks, and furthermore we will provide answers as to the mechanisms for Ski's effects. Ultimately, this research will translate to the development of novel reagents for the treatment of heart failure.