Integrin-linked kinase (ILK) signalling - a novel target for heart failure

• Applicant: Professor Dr. Wolfgang Rottbauer
• Subject Area: Cardiology, Angiology
• Term: from 2008 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 66045085

The precise signaling cascades that translate mutations in dilated cardiomyopathy (DCM) genes into the cardiomyopathic phenotype are only poorly understood, but of immense importance for the development of novel treatment strategies. In our attempt to further define the molecular pathology of Integrin linked kinase (ILK)-signalling associated dilated cardiomyopathy and evaluate its drugability, during the first funding period of this research project we identified a crucial role of the ILK interacting proteins Affixin/ß-Parvin and PINCH in controlling cardiac contractility by warranting IPP (ILK-Parvin-PINCH) complex stability and IPP complex mediated protein kinase B (PKB)-signaling. Remarkably, cardiac contractility in IPP-complex heart failure zebrafish can be restored either by over-expression of constitutive-active PKB or compounds that specifically activate PKB in the heart, implicating PKB as a novel therapeutic target to treat IPP-complex associated heart failure. Furthermore, our cardiac ILK interactome studies revealed a novel, IPP-complex and hence PKB-independent signaling pathway, the so-called FAK-complex. In the second funding period we now aim to (1) elucidate the in vivo role of IPP-complex-independent ILK pathway components, (2) decipher the common molecular determinants/network components and hubs of IPP-complex-dependent and IPP-complex-independent heart failure by a systems biology approach, (3) specifically dissect the relevance of ILK´s kinase activity on heart function using the already established ILK-transgenic zebrafish lines and finally (4) identify novel potential heart failure therapeutics by high-throughput in vivo small compound screening on IPP-complex-dependent zebrafish heart failure mutants on our established screening platform.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Hans A. Kestler