Systems Medicine and Mechanobiology

ERC Advanced – MechAGE

Osteoporosis, one of the most prevalent degenerative diseases, is characterized by a reduction in bone mass and increased fracture risk and has been partly attributed to the decrease in mechanical usage of the skeleton. A detailed understanding of the molecular mechanisms governing load-regulated bone remodeling could therefore lead to the identification of molecular targets for the development of novel therapies. Bone remodeling is a multiscale process mediated through complex interactions between multiple cell types and their local 3D environments. However, the underlying mechanisms of how cells respond to mechanical signals – a process typically referred to as mechanobiology – are still unclear.

Our Goal

By combining single-cell “omics” technologies with well-established tissue-scale models of bone mechanobiology, the MechAGE project proposes to develop the technology required to allow spatially resolved in vivo single-cell mechanomics of bone adaptation and regeneration. The project also aims to transfer this mechanomic knowledge to clinical applications in the context of systems medicine.

Our Expertise

We combine expertise from different disciplines (e.g. biology, engineering, informatics, veterinary medicine) allowing a multi-scale and multi-disciplinary approach combining in vivo models with in silico modelling and omics technologies. CRISPR/Cas technology will be exploited to generate fluorescent reporter mice to identify the different cell types involved in the bone remodeling process. By combining RNA-sequencing of single cells isolated by laser-capture microdissection with micro-finite element analysis and time-lapsed in vivo micro-CT, MechAGE will link the transcriptome of hundreds of single cells to their local mechanical in vivo environment (LivE). This will allow investigation of molecular responses of the cells to LivE changes with aging in established mouse models of bone adaptation and regeneration. In addition to in vivo mechanomics, MechAGE proposes to use cellular and multiscale computational modeling to run in silico simulations of real-world events for better understanding of diseases of aging in mice and to maximize the use of the high quality in vivo mechanomic data. Findings from MechAGE will lead to a systems level understanding of the spatio-temporal regulation of gene expression during the process of load-induced bone adaptation and regeneration in the aging mouse.

Acknowledgments

The MechAGE project In Vivo Single-Cell Mechanomics of Bone Adaptation and Regeneration in the Aging Mouse currently receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 741883). More project related information can be found on external pageCordiscall_made.