ROLE OF MELUSIN IN CARDIOMYOPATHIES AND HEART FAILURE

Dilated cardiomyopathy is a disorder caused by inadequate blood pumping capacity and frequently leads to heart failure, the most common cause of death in developed countries. This pathology can be caused by a sporadic or familiar genetic defect and it occurs in consequence of pathologies such as myocardial infarct, hypertension, or valve disorders. In this case the onset of cardiomyopathy is due to specific genetic conditions that favour the evolution of the pathology. Identification of such genes represents a major challenge of molecular cardiology. We have recently identified the Melusin gene coding for a muscle and heart specific protein. By inactivating the melusin gene, we have generated melusin-null mice which develop dilated cardiomyopathy only when exposed to experimental conditions mimicking chronic hypertension. Preliminary results obtained in the laboratory, indicate that melusin, when over-expressed in the heart of transgenic mice, can protect from heart dilation in response to hypertension. With this project we will analyze the functional properties of hearts expressing high level of melusin in different experimental conditions and test the feasibility of a melusin-based gene therapy approach to prevent heart failure in mice model systems. A second aspect will be to establish the role of mutation/polymorphisms detected in the human melusin gene of patients affected by dilated cardiomyopathy in the development of pathology. A third aspect will be to dissect the structural properties of the protein and the molecular mechanisms involved in the ability to protect from dilated cardiomyopathy. To this purpose we will also analyze the ability of melusin to affect the activity of other genes. These studies will allow to define some of the mechanisms that underlie the onset of heart failure, and provide information on possible new approach to prevent this pathology.