SYSTEMATIC ANALYSIS OF TGF-ß SIGNALING AND ACTIVATION IN LIVER FIBROSIS

Abstract

Transforming Growth Factor-ß (TGF-ß) is a key cytokine in liver fibrosis. It is expressed in its latent form and needs to be activated to induce cellular responses. Thus, It is important to understand the TGF-ß signaling pathway as well as the activation process of TGF-ß. Computational modeling of TGF-ß signaling pathway and activation have also been built. We found a lack of understanding of the negative regulations of TGF-ß pathway, and integration of TGF-ß pathway and TGF-ß activation network. In this study, we first analysed negative regulatory mechanisms in TGF-ß pathway at a cellular level with tightly coupled computational modeling and biological experiments and a novel feedback mechanism was discovered. Then we developed algorithms that allow us to integrate the extracellular TGF-ß activation network and intracellular TGF-ß pathway at a cell-population level. In addition, we studied the spatial behavior of the bistability in TGF-ß activation network at a tissue level.