Grant: Project Grant

Heart disease is the primary cause of death in the western world. Cardiac fibrosis is a stiffening of the heart caused by many forms of heart disease. Fibrosis dramatically increases the risk of death and disability independently of other risk factors (up to 17 times), yet no treatments for cardiac fibrosis are available to patients. Our laboratory has identified a protein (scleraxis) as a powerful cause of fibrosis, and our initial data has indicated that interfering with scleraxis can reduce fibrosis. We hypothesize that blocking scleraxis in the heart is beneficial for heart disease patients. To control scleraxis in the heart, we propose to study the cell signals that regulate scleraxis production to identify new drug targets. We will also test existing drugs that have shown beneficial effects on fibrosis, as well as novel scleraxis-directed treatments, for their ability to block scleraxis and fibrosis. Extending our preliminary data, we will test four aims: Aim 1: we will define the mechanism by which angiotensin II, a hormone driver of high blood pressure and fibrosis, increases fibrosis by activating the scleraxis gene. Aim 2: we will test existing drugs (angiotensin II inhibitors - ACEi/ARB) that have shown beneficial effects on fibrosis for their ability to reduce scleraxis levels, and show that these drugs lose their efficacy when excessive scleraxis is made. Aim 3: using mouse models, we will demonstrate that deleting the scleraxis gene reverses heart fibrosis even when the disease is well-established. Aim 4: we will test the ability of a novel scleraxis mutant, developed in our lab, to interfere with normal scleraxis in the heart in order to reduce fibrosis. These results will reveal new details of how scleraxis causes cardiac fibrosis, will provide crucial supporting evidence for the eventual adoption of ACEi/ARB as treatments for this condition, and will demonstrate the efficacy of our scleraxis mutant as a potential new treatment for fibrosis.