Multiscale modeling of biological systems: An integrative approach

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The application of mathematical and computational models to biology is an exciting and novel area of research in Applied Mathematics. The main objective of this research is to gain a more fundamental understanding of the complex processes of biological systems by integrating experimental studies and quantitative approaches. The epithelial-mesenchymal transition (EMT) is a biological process wherein epithelial cells undergo multiple biochemical changes and adopt mesenchymal features including an enhanced capacity for migration, invasiveness, and elevated resistance to apoptosis. This transition is a critical process during embryonic development, wound healing and metastasis. Further, recent studies have linked EMT with the acquisition of stem cell like characteristics in normal and neoplastic cell populations. Tissue microenvironmental factors, such as hypoxic conditions, may also induce EMT in cells. Hypoxia-induced transition seems to be accompanied by increased activation of Akt and subsequent downstream signaling. Moreover, mitochondrial production of reactive oxygen species is increased during hypoxia, resulting in the induction of EMT. In addition, the cancer stem cell phenotype is regulated by the microenvironmental factors hypoxia and acidity. This proposal aims to apply an integrative approach to provide a three-faceted study of the links between EMT, stem cells and tissue microenvironment. The available experimental data will be combined with existing and novel mathematical models to investigate the effects of hypoxia, acidity and EMT on properties of stem cells. These mathematical models range from deterministic and stochastic differential equations to numerical simulations of the system. This proposal aims to study (1) the effects of tissue microenvironmental factors on EMT and SCs, (2) the role of cell metabolism and antioxidants on EMT, and (3) the molecular links between EMT, SCs, and other related pathways.