Integrating at Sub-Cellular Level the Biochemical and Biomechanical Signals with Stochasticity to Study the Regulation of Tissue Growth

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The goal of this research is to understand how the biochemical signals and cell mechanics coordinate with each other to regulate tissue growth in achieving specific shape and robust size during the development. Growth regulation remains an unsolved mystery and a grand challenge for both developmental biology and regenerative medicine. Uncontrolled tissue growth can result in abnormal development and fatal diseases including cancer. Mathematical models offer an important new tool both to simulate biological systems and to test hypotheses in growth control mechanisms, currently difficult or impossible for experiments alone. This project will investigate mechanisms in growth regulation, including those that are difficult to test by using existing models, by developing a novel mathematical model incorporating biochemical signals and cell mechanical properties, as well as the interaction between them. By applying this model to a classical biological system, it will provide novel insights into the fundamental principles of growth control. UC Riverside is a Hispanic-serving institution with diverse student background. This research will engage undergraduate and graduate students in interdisciplinary projects and incorporate emerging results into coursework. Outreach activities, including seminars, workshops, and summer research programs, will be coordinated with department of mathematics, Interdisciplinary Center for Quantitative Modeling in Biology at UC Riverside, and community colleges in the area of southern California. Cells response to both chemical and mechanical signals to coordinate the growth and proliferation during the tissue development, such that the overall shape and tissue size can be obtained precisely with robustness. The Drosophila wing disc, an epithelial primordial organ that later forms the adult fruit fly wing, features a relatively simple geometry, limited number of cells, rapid growth, and a well understood molecular signaling network based on molecules conserved in other developmental systems. Studying this classical biological system can reveal underlying general mechanisms of growth regulation, applicable in other developmental systems. The main goal of this interdisciplinary research is to develop a coupled mechanochemical model at sub-cellular level in a mechanistic way for the wing disc tissue. Different morphogens acting in orthogonal directions as well as an intracellular gene regulatory network will be considered. Sub-cellular mechanical properties will be taken into account by using an advanced subcellular element model involving different cell types. The interaction between cell stiffness, cell-cell adhesion and biochemical signals will be included in this multiscale framework. This model will be applied to test the hypothesis that the rate of cell growth is determined by the temporal change in biochemical signals and the hypothesis that uniform growth is achieved by molecular cues and mechanical feedback, suggested by experimental data. This coupled model will allow exploration of the new mechanisms for spatially homogeneous growth and the asymmetric shape of the wing disc pouch, as well as investigation of the effects of stochasticity in biochemical or/and biomechanical signals on growth control mechanisms. This project is funded jointly by the Division of Mathematical Sciences Mathematical Biology Program and the Division of Molecular and Cellular Biosciences Cellular Dynamics and Function Program.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.