Grant: Doctoral Research Award - PA: Regional Partnerships Program - Manitoba

When the heart becomes damaged (e.g. heart attack) or must overcome increased resistance to pumping (high blood pressure), it must work harder to maintain its normal output of blood. In response to increased workload, heart cells enlarge in an attempt to compensate. For reasons not fully understood, there is also elevated deposition of strong fibres, made primarily of the protein collagen, within the heart wall ("cardiac fibrosis"). This process stiffens the heart and impairs contraction and relaxation, resulting in heart failure. We recently demonstrated that a regulatory protein called scleraxis, normally found in collagen-rich tissues like tendons and heart valves, is also made by the heart cells responsible for fibrosis- cardiac fibroblasts and myofibroblasts. Furthermore, scleraxis directly controls the synthesis of collagen proteins. We hypothesize that not only is scleraxis sufficient to control this synthesis, it is also necessary- if scleraxis is not present, there will be less fibrosis. We will test this hypothesis by surgically causing fibrosis in mice lacking the gene encoding scleraxis. If our hypothesis is correct, these mice will exhibit less fibrosis than those with an intact scleraxis gene. There are no publicly- available therapies specifically targeting cardiac fibrosis as yet despite its drastic impact on patient outcomes. This is due to an incomplete understanding of the regulatory pathways involved in fibrosis. This work will identify scleraxis as a required regulator of collagen synthesis in the heart, and thus as a potential target for drug therapy.