PhD: Investigating the biomechanics of craniofacial development

The shape of the vertebrate skull is dictated by genetic and environmental factors. Whilst we are beginning to unravel the genetic contribution, we still understand little about how environmental factors such as mechanical loads influence skeletal development and form. Nowhere is this more evident than in the vertebrate skull, where intrinsic mechanical loads are generated during embryonic development via adductor muscle contraction and the expanding braincase. The aim of this project is to determine how differences in craniofacial biology between juvenile, adult and aged wild type and mutant zebrafish phenotypes with disrupted loading environment lead to differences in jaw mechanics, and what this tells us about the influence of mechanical loads on skeletal evolution, development, maintenance and ageing. The project focuses on two mutant phenotypes: arid1b, a genetic mutation that is known to cause cleft palate and other facial deformities in humans and manifests as facial deformities in zebrafish; and Chst11, known as skeletor, which demonstrates an early ossification phenotype leading to a precociously robust skeleton and potentially increased jaw musculature. The student will use cutting edge techniques to identify the changes at a morphological level (computed tomography, contrast enhanced CT), at a cellular level (using live imaging of transgenic reporters for bone, cartilage, and connective tissue, and at the level of matrix organisation (second harmonic generation, electron microscopy, cutting edge live MRI imaging of fish with collaborator Holmes in Glasgow). Full training will be provided in all methods. Together these techniques will allow us to quantity the sequence of events that lead to altered craniofacial ossification. Using the engineering analysis technique finite element analysis, the student will conduct biomechanical simulations of jaw function to determine the impact of ageing and mutant phenotypes on jaw function.
The project will be divided between host labs with expertise in computational biomechanical modelling and craniofacial / skeletal development. This research relates to novel work by the supervisors and current students and postdocs on mechanosensitive genes and developmental biomechanics in zebrafish (Brunt et al. 2015, 2016). We have shown that mechanical loads during the very early stages of zebrafish development are required to generate and maintain a normal working jaw joint. The project will generate high impact publications and equip the student for a multidisciplinary career in mechanobiology, evolutionary developmental biology and/or biophysical modelling in academic or industry. It will suit a student with a background in organismal or cellular biology, biophysics or engineering.