COMPLIMB · A computational tool to elucidate the mechanobiological regulation of limb development
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-05-06 → 2022-05-05
- EU contribution
- €245,732
- Participants
- 2
- Scheme
- MSCA-IF-GF
Lines connect the coordinator with its partners.
Results in brief
A computational tool to elucidate the mechanobiological regulation of limb development
Congenital limb malformations affect between 0.2-0.9% of live births in Europe. The correct formation of limbs and their joints is critical for healthy function in adult life. Yet, important aspects of joint formation are still not fully understood. For example, forces from muscle contractions and motion are critical to creating a properly shaped joint, but it is unclear how cells sense and respond to these mechanical cues. Understanding the role of mechanical stimuli in joint formation can help identify when and how pathological conditions arise that result in malformations, and potentially provide clues on how to avoid or correct joint deformities. Ultimately, a better understanding of joint formation could inform therapies to correct joint deformities, as well as contribute to the development of preventive strategies for congenital limb defects. The main goal of the CompLimb project was to determine the role of mechanical stimuli and mechanosensitive growth regulators driving joint formation in vertebrates. To achieve this goal, we used a combined experimental and computational approach. Limb formation has been widely studied in axolotl salamanders (Ambystoma mexicanum), as they regrow limbs throughout their life. Experiments on regenerating axolotl limbs provide information on how altering the cell’s ability to sense and respond to mechanical stimuli affects joint shape as well as the location and timing of molecular expression critical to joint formation. Predictive computational models informed by the experimental findings allow us to explore potential physical mechanisms of normal and pathological joint formation.
Data: CORDIS, © European Union
Project objective
Understanding the roles of motion and mechanotransduction in joint formation holds promise for the study and treatment of joint deformities in humans. Joint development has been widely studied in axolotls (Ambystoma mexicanum), as these animals regrow whole limbs throughout their life. Axolotl limbs are morphologically similar to human limbs and utilize the same biological rubrics as ontogenic growth. To draw from the therapeutic potential of these similarities, we propose to build a multi-scale multi-physics computational model for the prediction of vertebrate limb development. Our model will be based on in vivo data obtained using novel imaging techniques via NSF-funded experiments on axolotl limb growth, and will be utilised to determine the physical mechanisms of normal and pathological joint morphogenesis. To this end, in AIM 1 we will build a finite element model of growth at the tissue level to study how specific changes in limb motion regulate joint morphology. Next, in AIM 2 we will build a model of growth at the molecular level to determine how biochemical and biomechanical signalling pathways interact during normal and pathological joint development. Finally, in AIM 3 we will integrate both experimental and computational data from the different length scales into a single multi-scale mechano-biochemical model of vertebrate limb growth. A computational model that links the biomechanics and biochemistry of normal and pathological limb development at the subcellular, cellular and tissue scales is a powerful predictive tool. We envisage this tool will be utilised to optimise treatment therapies for joint deformities and better inform the preventive screening of congenital defects in humans.
Original text from CORDIS.
Participants
- UNIVERSITAT POLITECNICA DE CATALUNYA · BARCELONACoordinatorSpain
- NORTHEASTERN UNIVERSITY · Boston MaUnited States
Links
Data: CORDIS, © European Union