Titin Signals · Molecular dissection of titin-based mechanisms in charge of cardiomyocyte dysfunction in terminal feart failure

Molecular dissection of titin-based mechanisms in charge of cardiomyocyte dysfunction in terminal feart failure

Cardiovascular diseases (CVD) cause over 1.8 million deaths in the European Union yearly, resulting in the overall estimated burden of 210 billion Euros in 2016. Half of the costs are due to health care expenses, one quarter due to productivity losses, and the remaining amount is associated with the informal care of people with CVD. Among CVDs, the burden of heart failure (HF) is substantial and likely to grow: at present, 15 million people living with heart failure in Europe. HF is the leading cause of hospitalization in people over the age of 65. The current management of HF mainly targets the secondary pathophysiological adaptations, but not the myocardial dysfunction itself and is not efficient. Overall, 50% of patients are dead within four years. Thus, there is a massive demand for new therapy and diagnosis methods. Identification of new HF therapy targets within the cardiomyocyte contractile apparatus would contribute to better management of HF and would lead to the reduction of CVD associated costs. Titin molecule is a central player in cardiovascular health and disease. Titin is a giant protein, longer than one micrometer, that functions as tightly regulated molecular spring, governing biomechanical properties of striated muscle, including the heart. Titin not only contributes to biomechanical properties of cardiac muscle but is a core site for the functional integration of sarcomeric signaling. Numerous animal models and patient biopsy studies have reported the induction of proteins binding to the titin N2A spring region under myocardial stress conditions, including members of the CARP family (Cardiac Ankyrin Repeat proteins). Therefore, the titin N2A-CARP signaling axis may represent a target for HF therapeutic strategies. This multidisciplinary project aims to develop novel HF therapeutic strategies based upon modulating the N2A-CARP signaling axis. This principle goal is pursued by different methodological approaches, including the development and phenotypic characterization of the N2A deficient mouse model, the development of Adeno-associated viral vectors for cardiac-specific CARP overexpression, screens for small molecule modulators of N2A-CARP interaction, and finally a structural characterization of the titin N2A-CARP complex. This multidisciplinary approach will provide me with in-depth training in translational molecular cardiology and provide novel translational insights into heart failure therapy.

Data: CORDIS, © European Union