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A Quantitative Kinetic Model for Genes Regulatory Network Using Single-Cell Mechanomics
Cell signalling pathways are important regulators of bone growth and remodelling. Yet, a quantitative detailed understanding of these molecular processes is still missing in the context of bone biology. The goal of this project is to model quantitatively the kinetics of the genes regulatory network.
Keywords: In silico model, Bone Remodelling, Genes, Mechanomics, Simulation, Programming
Bone tissue is continuously adapting to mechanical and chemical cues through changes in its trabecular microstructure, achieved through the process of bone remodelling. The Basic Multicellular Unit (BMU), a group of cells which is responsible for bone remodelling, includes osteoblasts and osteoclasts, which are bone forming and resorbing cells, respectively. These cells are regulated through biochemical signals secreted by mechanically sensitive cells called osteocytes, which are confined inside the bone in cave-like holes called lacunae. Eventually, these local biomechanical and biochemical signals affect the BMUs, which in turn change bone mass and local bone morphology. Osteoblast and osteoclast function are regulated by specific pathways such as the Wingless-INT(Wnt) signalling pathway or Bone Morphogenetic Protein (BMP) signalling. With ageing, these pathways tend to be not well regulated leading to pathologies like osteoporosis.
In our group there is a large project with access to in vivo data combining RNA-sequencing (RNA-seq) of single cells isolated by laser-capture microdissection (LCM). With these tools, genetic information related to the cells involved in bone remodelling can be extracted and the effect of the genes on the cells can be studied in detail. This knowledge will be combined with the time-lapsed images obtained from micro-computed tomography (micro-CT) scans of mouse vertebra; these scans provide a quantification of bone in a three-dimensional (3D) way.
A quantitative kinetic model for genes regulatory network could enhance the information provided from the experimental data, allowing the potential genetic expression and the genetic interrelation of the cells to be predicted, giving insights into the regulation of bone mass and development. This model, based on mathematical tools like ordinary differential equations (ODEs), may faithfully reproduce molecular information for this purpose.
Three-dimensional multiscale in silico models, based on cell-to-cell signalling, have been shown to be powerful tools in exploring the effects of signalling on fracture healing in mice. For the proposed project, this developed model will be extended at the molecular scale to include genes that play an important role in the Wnt-beta-catenin pathway and are not currently implemented in the model. This network will then be used to substitute the cell-type-specific mechanomic profiles developed previously, in order to account for the healthy and ageing conditions which develop through the gene expression in the cells. This network will be then tested and simulated using a small domain which has the same resolution of the micro-CT scans. Eventually, each cell in the model will be characterized by a set of genes to be validated with the in vivo datasets related to the molecular activity, the local remodelling activity and the associated mechanical environment which will be gathered in our group.
Bone tissue is continuously adapting to mechanical and chemical cues through changes in its trabecular microstructure, achieved through the process of bone remodelling. The Basic Multicellular Unit (BMU), a group of cells which is responsible for bone remodelling, includes osteoblasts and osteoclasts, which are bone forming and resorbing cells, respectively. These cells are regulated through biochemical signals secreted by mechanically sensitive cells called osteocytes, which are confined inside the bone in cave-like holes called lacunae. Eventually, these local biomechanical and biochemical signals affect the BMUs, which in turn change bone mass and local bone morphology. Osteoblast and osteoclast function are regulated by specific pathways such as the Wingless-INT(Wnt) signalling pathway or Bone Morphogenetic Protein (BMP) signalling. With ageing, these pathways tend to be not well regulated leading to pathologies like osteoporosis. In our group there is a large project with access to in vivo data combining RNA-sequencing (RNA-seq) of single cells isolated by laser-capture microdissection (LCM). With these tools, genetic information related to the cells involved in bone remodelling can be extracted and the effect of the genes on the cells can be studied in detail. This knowledge will be combined with the time-lapsed images obtained from micro-computed tomography (micro-CT) scans of mouse vertebra; these scans provide a quantification of bone in a three-dimensional (3D) way. A quantitative kinetic model for genes regulatory network could enhance the information provided from the experimental data, allowing the potential genetic expression and the genetic interrelation of the cells to be predicted, giving insights into the regulation of bone mass and development. This model, based on mathematical tools like ordinary differential equations (ODEs), may faithfully reproduce molecular information for this purpose. Three-dimensional multiscale in silico models, based on cell-to-cell signalling, have been shown to be powerful tools in exploring the effects of signalling on fracture healing in mice. For the proposed project, this developed model will be extended at the molecular scale to include genes that play an important role in the Wnt-beta-catenin pathway and are not currently implemented in the model. This network will then be used to substitute the cell-type-specific mechanomic profiles developed previously, in order to account for the healthy and ageing conditions which develop through the gene expression in the cells. This network will be then tested and simulated using a small domain which has the same resolution of the micro-CT scans. Eventually, each cell in the model will be characterized by a set of genes to be validated with the in vivo datasets related to the molecular activity, the local remodelling activity and the associated mechanical environment which will be gathered in our group.
The goal is to establish a quantitative kinetic model for genes regulatory network using single-cell mechanomics. With this model, we want to better understand the cell signalling of bone multicellular units in bone remodelling. The algorithms will be coded in C/C++ and added into the model. Our lab uses a programming framework built in Python and C++, the former is the preferred language in our group. As a result, the C++ code will be wrapped in Python and run through Python scripts.
The goal is to establish a quantitative kinetic model for genes regulatory network using single-cell mechanomics. With this model, we want to better understand the cell signalling of bone multicellular units in bone remodelling. The algorithms will be coded in C/C++ and added into the model. Our lab uses a programming framework built in Python and C++, the former is the preferred language in our group. As a result, the C++ code will be wrapped in Python and run through Python scripts.
Daniele Boaretti (daniele.boaretti@hest.ethz.ch) Institute for Biomechanics, ETH Zurich, Professorship Ralph Müller
Daniele Boaretti (daniele.boaretti@hest.ethz.ch) Institute for Biomechanics, ETH Zurich, Professorship Ralph Müller