The calcium and integrin binding protein (CIB)1 as therapeutic target in heart failure

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Pathological overload of the heart for example during arterial hypertension, aortic valve stenosis or myocardial infarction triggers cardiac hypertrophy and ultimately heart failure. In Europe around 10 million people suffer from heart failure, which is still associated with high morbidity and mortality. Therefore, new therapeutic strategies are needed. We demonstrated in our previous work that the adaptor protein CIB1 in cardiomyocytes specifically promotes pathological, maladaptive hypertrophy, but not physiological (adaptive) hypertrophy as it occurs for example in athletes, where it is not associated with disease. Consequently, genetic deletion of CIB1 in mice protects against the development of pathological hypertrophy and heart failure. CIB1 promotes cardiomyocyte growth by recruiting the prohypertrophic phosphatase calcineurin to the cell membrane where it can get activated within a specialized microdomain. Within this proposal we aim to establish translational therapeutic concepts to inhibit CIB1 in the myocardium. First, we want to downregulate CIB1 with a short-hairpin RNA (shCIB1) in a gene-therapeutic approach. For this purpose we developed a strategy to overexpress shCIB1 with an adeno-associated virus (AAV) 9. We now aim to test the effects of AAV-shCIB1 on hypertrophy and heart failure development after experimental aortic constriction or myocardial infarction in mice. Secondly, we aim to identify a chemical component that interrupts the association of CIB1 and calcineurin and consequently inhibits cardiac hypertrophy and heart failure. We established a mammalian two-hybrid assay that allows quantification of the interaction between CIB1 and calcineurin. With the help of the Leibniz Institute of Molecular Pharmacology in Berlin we want to screen 40.000 defined chemical substances for an inhibitory effect on the CIB1/calcineurin interaction. Positive substances will be tested for their antihypertrophic and calcineurin inhibiting effects at first in isolated cardiomyocytes. Our long-term goal is to develop these translational concepts towards clinical application in patients with heart failure.