? In vertebrates, segmentation during early embryogenesis forms somites, recurring tissue modules, distributed along the anterior-posterior axis. Segmental structures give rise to the ribs, vertebrae, limbs, associated muscles, and central and peripheral nervous system. Failures in segmentation can be lethal or cause serious developmental abnormalities. Somitogenesis relies on a molecular clock, growth factor gradients and the expression of cell-adhesion and extracellular matrix (ECM) molecules. Segmentation requires complex, large-scale (millimeter) coordinated movement of cells and ECM. Despite increasing knowledge of the molecular mechanisms underlying segmentation, the interplay ? of molecular-, cell- and tissue-level mechanisms during somitogenesis remains obscure. Because of the tight feedback between subcellular and large-scale processes, no single-scale model can simulate somitogenesis. Current models address only the subcellular or macroscopic levels and do so separately. A successful multiscale model will answer one of developmental biology's great open problems: how do the molecular mechanisms of fate determination couple to large-scale tissue deformations? The proposed work will test the hypothesis that during segmentation, physical forces and biomaterial properties must coordinate with a moving biological oscillator, the segmentation clock, for successful somitogenesis. We will both model and conduct experiments on key developmental mechanisms ranging from local regulation of cell adhesion proteins (micrometers) to global tissue deformations (millimeters). We will develop novel theories and modeling approaches to bridge these scales. Our methodology has four major components: 1) Identifying (discovering) mechanisms and relevant models at each scale. 2) Determining the parameters for each level of model. 3) Validating ? model results. 4) Testing model predictions of normal and abnormal behaviors, e.g. inhibition or overproduction of adhesion molecules. The techniques and insights the research will produce will apply to other developmental processes. The software we develop will form the core of an open-source, multiscale and general purpose Tissue Simulation Toolkit, which other researchers can apply to this and other developmental problems. The proposed research contributes to public health by addressing the causes of a significant subset of the developmental malformations which occur in approximately 150,000 infants born each year in the USA (1 out of 28 births). Disturbing somite formation results in Klippel-Feil syndrome.spondylocostal dysostosis.Jarcho-Levin syndrome, congenital scoliosis and kyphosis, Goldenhar syndrome, and spina bifida, among others disorders. Studying the developmental ? mechanisms in vertebral patterning will aid in the identification of protective or potentially disruptive factors for normal somitogenesis and could potentially impact treatments for the prevention of vertebral patterning disorders. ? ?
| Ward, Lizzy; Pang, Angel S W; Evans, Susan E et al. (2018) The role of the notochord in amniote vertebral column segmentation. Dev Biol 439:3-18 |
| Ward, Lizzy; Evans, Susan E; Stern, Claudio D (2017) A resegmentation-shift model for vertebral patterning. J Anat 230:290-296 |
| Somogyi, Endre; Glazier, James A (2017) A MODELING AND SIMULATION LANGUAGE FOR BIOLOGICAL CELLS WITH COUPLED MECHANICAL AND CHEMICAL PROCESSES. Symp Theory Model Simul 2017: |
| Belmonte, Julio M; Swat, Maciej H; Glazier, James A (2016) Filopodial-Tension Model of Convergent-Extension of Tissues. PLoS Comput Biol 12:e1004952 |
| Somogyi, Endre; Sluka, James P; Glazier, James A (2016) Formalizing Knowledge in Multi-Scale Agent-Based Simulations. Model Driven Eng Lang Syst 16:115-122 |
| Belmonte, Julio M; Clendenon, Sherry G; Oliveira, Guilherme M et al. (2016) Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease. Mol Biol Cell 27:3673-3685 |
| de Almeida, Rita M C; Clendenon, Sherry G; Richards, William G et al. (2016) Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD. Hum Genomics 10:37 |
| Stern, Claudio D; Piatkowska, Agnieszka M (2015) Multiple roles of timing in somite formation. Semin Cell Dev Biol 42:134-9 |
| Somogyi, Endre T; Bouteiller, Jean-Marie; Glazier, James A et al. (2015) libRoadRunner: a high performance SBML simulation and analysis library. Bioinformatics 31:3315-21 |
| Swat, Maciej H; Thomas, Gilberto L; Shirinifard, Abbas et al. (2015) Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D. PLoS One 10:e0127972 |
Showing the most recent 10 out of 57 publications
