Targeting Sox9 in cardiomyopathy

Aim 1: To define molecules and pathways that lead to fibrogenic SOX9 activation in fibroblasts and endothelial cells and to define the SOX9 dependent secretome in both cell types. This will enable the identification of new strategies to counteract SOX9 or its crucial downstream targets in disease. This aim is divided into the following 3 sub-aims: Aim1.1. To screen the druggable genome for upstream regulators of SOX9 activation or inhibition, to define associated posttranslational modification if applicable, and to test the functional impact. Aim1.2 To screen a human ubiquitin/proteasome library for proteins that lead specifically to degradation of SOX9. Subsequently, investigate mechanisms of SOX9 degradation by the identified E3ligase/ubiquitinase. Aim 1.3 Investigating the SOX9 dependent secretome. Aim 2: To define the role of epicardial cell SOX9 for myocardial healing, scar expansion and ventricular remodeling and to develop translational strategies to target epicardial SOX9.