Grant: Operating Grant

The walls of the heart are strengthened by a supporting framework ("extracellular matrix") made primarily of a protein called collagen. In response to stresses such as high blood pressure, cells in the heart called myofibroblasts make additional collagen to strengthen the damaged heart wall and help the heart to maintain its function. After heart attack, a collagen-rich scar is formed to prevent rupture of the heart. However, matrix production is a double-edged sword - too much causes the heart walls to stiffen, impairing heart contraction and relaxation. Excessive collagen accumulation ("fibrosis") is a significant clinical challenge, affecting millions of patients worldwide. Drug treatments targeting fibrosis are lacking, due in part to the fact that we do not fully understand the fibrotic process. Designing drugs to target fibrosis requires a better understanding of how excess collagen is made. Our previous research indicates that a protein called scleraxis is an important new regulator of collagen synthesis. Our work shows that scleraxis directly activates the gene encoding a key cardiac collagen that is largely responsible for fibrosis. Furthermore, we have found that interfering with scleraxis leads to blockade of collagen production in isolated cells. The current proposal will expand on these discoveries by determining whether the loss of scleraxis will blunt collagen projection in animal models of high cardiac pressure and heart attack. This information is critical if we are to target fibrosis without affecting scar formation. We will test whether mice that lack the scleraxis gene become resistant to fibrosis, and whether lack of scleraxis impairs scar formation. We will also identify other genes regulated by scleraxis, and will determine how this regulation occurs. Our work will thus confirm scleraxis is a critical player in the progression of fibrosis, and a potential target for therapeutic anti-fibrosis drug design.