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Center for Nonlinear Studies |
Cellular responses are directed by mechanical and chemical cues, all under the regulation of a molecular network. Dysregulation of this molecular network results in aberrant cellular response, ultimately resulting in disease. Therefore, understanding how cellular responses are generated in response to different stimuli as a result of regulation at the molecular level is crucial for understanding disease and developing treatments. However, understanding the molecular machinery regulating cellular behavior by ‘wet-lab’ experiments and conceptual diagrams alone is difficult. This is because biological systems are composed of different spatial and temporal scales of complexity. In order to unravel the molecular scale mechanisms giving rise to cellular scale behaviors we need a quantifiable framework capable of generating biological insights and hypotheses by mechanistically linking multiple scales of complexity. Mathematical models based on physico-chemical principles serve as an excellent tool for understanding biological complexity. In this seminar I will discuss two such models developed to explain the molecular mechanisms underlying cellular mechanosensing and chemosensing. The first example is a mechanistic spatiotemporal model of the phospholipase C (PLC)/ protein kinase C (PKC) signaling pathway. This model characterizes the molecular scale mechanisms responsible for sensing and amplifying gradients of extracellular platelet derived growth factor during wound invasion by dermal fibroblasts. In addition, this molecular scale model will serve as one of the first steps towards understanding the multiscale nature of the proliferation phase of wound healing. The second example is a theoretical model that explains the different mechanosensory and mechanoresponsive behaviors observed in Dictyostelium cells. The model features a multiscale description of myosin II bipolar thick filament assembly that includes cooperative and force-dependent myosin–actin binding, and identifies the feedback mechanisms hidden in the observed mechanoresponsive behaviors of Dictyostelium cells during micropipette aspiration experiments. These feedbacks provide a mechanistic explanation of cellular retraction and hence cell shape regulation.
Host: William Hlavacek