Project 460085

The health problem that we will be studying is cardiac remodeling. In response to heart disease, the properties of the heart adapt, a process called "remodeling". Remodeling can be beneficial, but when excessive or prolonged it can be harmful. In response to disease or stress, the heart tends to remodel in an initially adaptive fashion, but like in many situations, there "is no free lunch" and when the stress is prolonged, remodeling causes serious adverse consequences that cause heart function to deteriorate. The ways in which the heart remodels are important determinants of the outcome of heart disease and many clinically effective treatments have been discovered through their beneficial effects on heart remodeling in animal models of human disease. We have found that a hormone called calcitonin, previously unknown to be active in the heart (but an important product of the thyroid gland), can be produced in the heart and protect against adverse cardiac remodeling. We have discovered that, in mice, when the receptors through which calcitonin acts called ("calcitonin receptors") are knocked out, the animals show enhanced adverse remodeling in response to the kinds of stress situations that cause human heart disease. This observation suggest that signalling through the calcitonin receptor occurs in the heart and protects the heart against adverse remodeling In this project, we aim to find out how calcitonin-receptors produce their protective actions in heart disease and how this knowledge might be used to prevent or treat the development of heart disease in man.