The goal of this proposal is to obtain a global understanding of how cells establish and control their shapes by integrating the molecular and mechanical aspects of cellular morphogenesis. This research will address a major gap in our current understanding of morphogenesis, namely the disconnect between the molecular and physical control of cell shape. Studies of walled cells, such as plant, fungal and bacterial cells, have shown that the mechanics of cell wall expansion and growth critically affect morphogenesis. Molecular biology studies have provided valuable information about the individual chemical species involved in shaping cells, but it is unclear how the molecular information is connected to the physical/mechanical processes that sculpt cells in space and time, rendering the connection between genotype and morphological phenotype virtually impossible. To bridge this gap, we propose a highly coordinated effort encompassing models of cell wall mechanics, experiments that measure and perturb key physical parameters such as new cell wall assembly and its material properties, and the development of a multi-scale computational framework to integrate the stochastic simulations of molecular events governing cell polarization and growth with finite element simulations of a coarse-grained model for the mechanics of cell wall expansion. Specifically, we will: (1) Develop a multiscale model of yeast mating projections that couples the dynamics of intracellular events to cell wall mechanics and growth. (2) Characterize experimentally the mechanical and molecular determinants of mating projection tip growth in S. cerevisiae. We will use the formation of mating projections in S. cerevisiae as a case study, because yeast combines the strengths of a genetic model organism with the simplicity of tip growth, a model system for the mechanics of cellular morphogenesis. (3) Develop a generic computational framework to bridge the mechanics of cell wall expansion to the dynamics of intracellular events. This will require algorithms for the coupling of physical and molecular processes on regions with moving boundaries, modeling of actin dynamics in spatial stochastic simulation, and hybrid mesoscopic/microscopic simulation.
By improving the understanding of how molecular events control the mechanics of the cell wall, the proposed work has the potential to advance the fields of medicine and drug development, particularly in the search for new antifungal and antibiotics, since various of these drugs target the mechanical integrity of cell wall of bacteria and fungi.
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