Grant: Operating Grant

The walls of the heart are strengthened by a supporting framework called the extracellular matrix, made primarily of a protein called collagen. In response to stresses such as high blood pressure or heart attack, cells in the heart called myofibroblasts make additional collagen, which strengthens the damaged heart wall and helps the heart to maintain its function. However, over time too much collagen can be made, causing the heart walls to stiffen and impairing heart contraction and relaxation. This excessive collagen accumulation (« fibrosis ») is a significant clinical challenge, affecting millions of patients worldwide. Drug treatments for fibrosis are limited and show modest effects. This is likely due to the fact that these drugs do not target fibrosis itself, but rather the underlying conditions. To design better drugs to specifically target fibrosis, we must better understand how and why excess collagen is made. Our previous research indicates that a protein called scleraxis is an important new player in the process of collagen synthesis. Our work shows that scleraxis directly regulates the gene encoding a key cardiac collagen that is largely responsible for fibrosis. The current proposal will expand on these discoveries by determining whether the loss of scleraxis will blunt collagen projection. To undertake this work, we will study mice in which the gene encoding scleraxis has been deleted. We will test whether these mice become resistant to fibrosis. We will also determine where and when scleraxis is active in the heart during the development of fibrosis. Finally, we will determine whether scleraxis interacts with other cellular pathways known to impact collagen formation, and if so, how this occurs. Our work will thus identify scleraxis as a critical player in the progression of fibrosis, and as a potential target for therapeutic anti-fibrosis drug design. This is a first and critical step towards the development of better treatments for fibrosis.