Identification of the role of the Rac1 activator Tiam1 in human cardiac fibroblasts with the help of engineered connective tissues

Cardiac Rac1 signaling has been recognized as a potential therapeutic target in heart diseases due to its role in cardiomyocyte hypertrophy and fibrosis. The omnipresence of Rac1 signaling throughout the body, however, does not allow for direct Rac1 targeting. We therefore believe that regulators of Rac1 are the better choice for future therapeutic strategies. In this context, we have identified by in vitro and in vivo experiments the Rac1 activator Tiam1 as an interesting option1,2, including preliminary data presented at the DGK spring meeting 20193. To further validate Tiam1 as a regulator of cardiac fibrosis, we want to investigate its role in engineered connective tissues (ECT) composed of human cardiac fibroblasts and collagen 1. We aim to investigate the impact of Tiam1 on the biomechanical properties of ECT under high and low mechanical stress as well as in the additional presence of a general activation of adrenoceptors (aim 1). We further want to understand how Tiam1 is involved in pro-fibrotic signaling and the regulation of remodeling (aim 2 and 3). Moreover, Tiam1 as a Rac1 activator is predestinated to play a role in the production of reactive oxygen species, which could contribute to paracrine signaling in the myocardium. There is however so far, no data available on the influence of Tiam1 on the production of ROS in human cardiac fibroblasts.