The ability of cells to divide, establish a polarization direction, and move by crawling requires the coordinated interactions of the cytoskeleton with membranes as well as with the signaling system organizing on membranes. A major challenge for the development of predictive mathematical and computational models of these mechanisms of subcellular organization is accounting of how highly specific interactions at the molecular level lead to the emergent collective behavior. We propose to address this complexity by employing powerful computational and modeling methods linking molecular to cellular scales, in close collaboration with experimentalists working on model systems that (i) reveal important cell biological functions and (ii) are amenable to quantitative approaches. The proposed research program will address mechanisms in cytokinesis, cell polarization and motility. A. Cytokinesis. We have previously modeled how the contractile ring in fission yeast forms through the condensation a broad band of membrane-bound nodes containing myosin and formin. These models represented nodes, which are large macromolecular complexes, as single units with the ability to polymerize and pull actin. Using input from super-resolution experiments and applying coarse- grained biophysical modeling and Bayesian inference methods, we propose to model the ultrastructure and dynamics of nodes, how this organization impacts their ability to capture and pull actin filaments, as well as the role of type V myosin. We will develop models to study how membrane delivery is distributed across the whole septum and how it coordinates with contractile ring constriction and tension. B. Cell polarization and ER organization. We will study how the Cdc42/Ras1 system establishes patterns with distinct spatial distributions of GEF and GAP regulators on cell membrane. Novel modeling methods will be developed to understand how the ER membrane is distributed subcellularly on cortical sheets adhered to the plasma membrane, cortical fenestrae anchored to eisosomes and internal tubular networks, altogether regulating cell polarization. C. Actin dynamics in motile cells. We will develop filament-level models of actin dynamics and organization in lamellipodia that account for their dendritic network structure, distributed turnover, force transmission and mechanical regulation of branching, severing and polymerization. In collaboration with the Watanabe group (Kyoto University), we will test these models by measuring turnover and flows near focal adhesions with single molecule imaging of actin and regulators.
We will study the dynamics of the actin cytoskeleton within cells, which regulates their shape and motion, such as during organism development, differentiation, neuron function, or cancer cell metastasis. To address the complexity of cellular dynamics, the project combines mathematical modeling with experimental studies by collaborators. If successful, this basic science would underpin future medical research based on an understanding of cellular function.
