There is a need for alternative methods to replace, reduce and refine (3R) animal experimentation. Combining experimental data from high-throughput in vitro studies with in silico modeling is a... Show moreThere is a need for alternative methods to replace, reduce and refine (3R) animal experimentation. Combining experimental data from high-throughput in vitro studies with in silico modeling is a promising approach to unravel the effect of chemicals on living cells and to gain a better understanding of the processes leading to adverse effects. Exposure to chemicals can activate various stress response pathways that limit the amount of cellular damage, help cells to recover or orchestrate irreversible cell fates such as apoptosis. In this thesis, we use experimental data and current knowledge on stress pathway activation and cell fate to create different types of computational models. With these models, we mathematically describe intracellular protein signaling cascades activated upon exposure to various compounds and their link to cell fate. In this way, we integrate molecular-level biological processes to cell-level phenomena such as cell cycle progression, senescence and necrosis, and generate new hypotheses about the mechanisms underlying adversity. Show less
Tissue Factor (TF) is a membrane protein that is responsible for the initiation of the coagulation. In addition to its coagulant activity, it can also signal through a member of G-protein coupled... Show moreTissue Factor (TF) is a membrane protein that is responsible for the initiation of the coagulation. In addition to its coagulant activity, it can also signal through a member of G-protein coupled receptor family, PARs, thus play a role in breast cancer growth and angiogenesis. The switch between signaling and coagulant TF regulated by the oxidation/reduction of an allosteric disulfide bond which resides in TF antigen. A decade ago, it was discovered that TF RNA can be alternatively spliced to form a soluble protein called Alternatively Spliced Tissue Factor (asTF). This protein is non-coagulant. However, it plays a major role in breast cancer growth via inducing cancer cell proliferation. The mechanism lying behind behind this phenomenon is asTF's capability to ligate integrins thus it can initiate integrin signaling. Moreover, both TF and asTF can synergize with estrogen pathway thus providing a complex regulation of breast cancer progression. Show less
