"Little is known concerning the mechanisms through which mechanical stimuli are transduced into regulatory signals within the cell. Gene expression can be regulated through alterations in nuclear architecture, modulating genome function. Mechanical load induces both nuclear distortion and alterations in gene expression. One putative transduction mechanism involves changes in gene expression in response to alterations in nuclear architecture as a result of mechanical perturbation of the cell. Additionally, remodelling of the nucleus occurs during stem cell differentiation, altering nuclear stiffness, and potentially influences nuclear architecture mediated mechanoregulation of gene transcription.In this project, the candidate will utilise the expertise in mechanobiology and functional genomics available at the host institution to investigate the potential for the micro-mechanical environment to modulate MSC differentiation fate via changes in nuclear architecture. Accordingly, the candidate proposes an ambitious and innovative program of research to test the following hypotheses:1. Mechanically-induced nuclear distortion causes alterations to the nuclear architecture and chromatin dynamics sufficient to alter gene transcription2. Mechanically-induced differentiation can lead to inheritable changes in the epigenetic state of chromatin regulating mesenchymal stem cell fate commitmentHe will employ a multidisciplinary approach building on the strengths of the host institution. The studies will utilise human mesenchymal stem cells in conjunction with state-of-the-art techniques for the mechanical perturbation of cells, functional analysis of nuclear organisation, biomechanical analysis, and functional genomic analysis; which will act to maintain and enhance the candidate’s position at the forefront of advances in this newly emerging field of genomic mechanobiology."