Grant: Project Grant

Cardiac fibrosis is stiffening of the heart due to excessive production of connective tissue in heart disease, dramatically increasing the risk of death independently of other risk factors. No treatments for cardiac fibrosis exist, in part because the underlying mechanisms remain unclear, and no therapies exist. In response to damage, heart cells called fibroblasts convert to myofibroblasts, which cause fibrosis. There are multiple kinds of fibroblasts in the heart, yet only some contribute to disease, and it is unclear how some persist to cause long-term disease. Our lab studies scleraxis, a protein we showed controls fibroblast conversion to myofibroblasts to drive fibrosis. However, it is unclear how scleraxis controls fibroblast populations, the genes they use, or their locations to cause disease. We will undertake 3 aims: Aim 1: we will characterize the heart's fibroblast populations, including their numbers and what genes they use, in a common model of heart disease; we will carry out these studies in normal mice, and in mice lacking the scleraxis gene to show the role of scleraxis in these populations. Aim 2: in fibroblasts and myofibroblasts, we will use a specialized method to capture and identify proteins that interact with scleraxis to determine how scleraxis works with its partners to promote fibroblast conversion. Aim 3: we will use cell tracing methods to examine the long-term fate of myofibroblasts in the damaged heart when scleraxis is present or absent, since we believe that scleraxis must be present for long-term survival. We track where these cells occur in the heart to learn how their locations change with disease. This study will reveal the critical role that scleraxis plays in governing myo/fibroblast populations in the heart, including during disease, and will greatly expand our understanding of how it interacts with other partners. The discoveries made here will help to identify new targets for anti-fibrosis drug development in future.